Solid forms of an hpk1 inhibitor

ABSTRACT

The present invention relates to salt forms of the hematopoietic progenitor kinase 1 (HPK1) inhibitors N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide and N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide, including methods of preparation thereof, where the compounds are useful in the treatment of HPK1 mediated diseases such as cancer.

FIELD OF THE INVENTION

The present invention relates to salt forms of the hematopoieticprogenitor kinase 1 (HPK1) inhibitorsN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,including methods of preparation thereof, wherein the compounds areuseful in the treatment of HPK1 mediated diseases such as cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M.C., et al.,Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M.C., et al., Genes Dev, 1996. 10(18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408),transforming growth factor receptor (TGF-β3R) (Wang, W., et al., J BiolChem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE₂ receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells. HPK1 isimportant in regulating the functions of various immune cells and it hasbeen implicated in autoimmune diseases and anti-tumor immunity (Shui,J.W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang, X., et al., JBiol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout mice were moresusceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). In human, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 is a drug target for enhancingantitumor immunity.

Inhibitors of HPK1 are currently being developed for the treatment ofcancer. For example, the moleculesN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideandN-(2-((2S,4S)-4-amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,and other small molecule inhibitors of HPK1 are reported in e.g., U.S.patert application Ser. No. 16/278,865 (published as US PatertPublication No. 2019/0382380). Accordingly, there is a need for newsolid forms and salts of HPK1-inhibiting molecules for preparingpharmaceutically useful formulations and dosage forms with suitableproperties related to, for example, facilitating the manufacture ofsafe, effective, and high quality drug products.

SUMMARY OF THE INVENTION

The present invention is directed to solid forms ofN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Compound 1) and salts thereof.

The present invention is further directed to salts of Compound 1. Thepresent invention is further directed to the phosphoric acid salt ofCompound 1, the hydrochloric acid salt of Compound 1, the L-(+)-tartaricacid salt of Compound 1, the malic acid salt of Compound 1, thecamphorsulfonic acid salt of Compound 1, the mandelic acid salt ofCompound 1, and the citric acid salt of Compound 1.

The present invention is directed to solid forms ofN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Compound 2) and salts thereof.

The present invention is further directed to salts of Compound 2. Thepresent invention is further directed to the phosphoric acid salt ofCompound 2 and the hydrochloric acid salt of Compound 2.

The present invention is further directed to crystalline forms of thesalts described herein. The present invention is further directed topharmaceutical compositions comprising a salt or crystalline formdescribed herein, and at least one pharmaceutically acceptable carrier.

The present invention is further directed to therapeutic methods ofusing the salts and solid forms described herein. The present disclosurealso provides uses of the salts and solid forms described herein in themanufacture of a medicament for use in therapy. The present disclosurealso provides the salts and solid forms described herein for use intherapy.

The present invention is further directed to processes for preparing thesalts and solid forms described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an XRPD pattern of Compound 1 Form I.

FIG. 2 shows a DSC thermogram of Compound 1 Form I.

FIG. 3 shows a TGA thermogram of Compound 1 Form I.

FIG. 4 shows an XRPD pattern of Compound 1 phosphate.

FIG. 5 shows a DSC thermogram of Compound 1 phosphate.

FIG. 6 shows a TGA thermogram of Compound 1 phosphate.

FIG. 7 shows an XRPD pattern of Compound 1 hydrochloride.

FIG. 8 shows a DSC thermogram of Compound 1 hydrochloride.

FIG. 9 shows a TGA thermogram of Compound 1 hydrochloride.

FIG. 10 shows an XRPD pattern of Compound 1 L-tartrate.

FIG. 11 shows a DSC thermogram of Compound 1 L-tartrate.

FIG. 12 shows a TGA thermogram of Compound 1 L-tartrate.

FIG. 13 shows an XRPD pattern of Compound 1 malate.

FIG. 14 shows a DSC thermogram of Compound 1 malate.

FIG. 15 shows a TGA thermogram of Compound 1 malate.

FIG. 16 shows an XRPD pattern of Compound 1 camsylate.

FIG. 17 shows a DSC thermogram of Compound 1 camsylate.

FIG. 18 shows a TGA thermogram of Compound 1 camsylate.

FIG. 19 shows an XRPD pattern of Compound 1 mandelate.

FIG. 20 shows a DSC thermogram of Compound 1 mandelate.

FIG. 21 shows a TGA thermogram of Compound 1 mandelate.

FIG. 22 shows an XRPD pattern of Compound 1 citrate.

FIG. 23 shows a DSC thermogram of Compound 1 citrate.

FIG. 24 shows a TGA thermogram of Compound 1 citrate.

FIG. 25 shows an XRPD pattern of Compound 2 phosphate.

FIG. 26 shows a DSC thermogram of Compound 2 phosphate.

FIG. 27 shows a TGA thermogram of Compound 2 phosphate.

FIG. 28 shows an XRPD pattern of Compound 2 hydrochloride.

FIG. 29 shows a DSC thermogram of Compound 2 hydrochloride.

FIG. 30 shows a TGA thermogram of Compound 2 hydrochloride.

DETAILED DESCRIPTION

The present invention is directed to, inter alia, solid forms ofN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Compound 1) and salts thereof, the structure of which is shown below.

Compound 1 is described in U.S. patert application Ser. No. 16/278,865(published as US Patert Publication No. 2019/0382380), the entirety ofwhich is incorporated herein by reference.

Compound 1 and its salts can be isolated as one or more solid forms. Thesolid forms (e.g., crystalline forms) described herein have manyadvantages, for example they have desirable properties, such as ease ofhandling, ease of processing, storage stability, and ease ofpurification. Moreover, the crystalline forms can be useful forimproving the performance characteristics of a pharmaceutical productsuch as dissolution profile, shelf-life and bioavailability. Forexample, the citric acid salt of Compound 1 is advantageous because itis highly crystalline, isolable as a single polymorph, non-hygroscopic,stable in aqueous formulations, and can be made reproducibly.

In some embodiments, the salt of Compound 1 is an acid salt ofCompound 1. In some embodiments, the acid is selected from phosphoricacid, hydrochloric acid, L-(+)-tartaric acid, malic acid,camphorsulfonic acid, mandelic acid, and citric acid.

In some embodiments, the salt of the invention is a phosphoric acid saltof Compound 1. The phosphoric acid salt form of Compound 1 is referredto herein as “Compound 1 phosphate salt,” “Compound 1 phosphoric acidsalt form,” “Compound 1 phosphoric acid,” or “Compound 1 phosphate.” Analternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidephosphate.

In some embodiments, the salt of the invention is a hydrochloric acidsalt of Compound 1. The hydrochloric acid salt form of Compound 1 isreferred to herein as “Compound 1 hydrochloride salt,” “Compound 1hydrochloric acid salt form,” “Compound 1 hydrochloric acid,” or“Compound 1 hydrochloride.” An alternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidehydrochloride.

In some embodiments, the salt of the invention is a L-(+)-tartaric acidsalt of Compound 1. The L-(+)-tartaric acid salt form of Compound 1 isreferred to herein as “Compound 1 L-tartrate salt,” “Compound 1L-(+)-tartaric acid salt form,” “Compound 1 L-(+)-tartaric acid,” or“Compound 1 L-tartrate.” An alternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideL-tartrate.

In some embodiments, the salt of the invention is a malic acid salt(e.g., L-(−)-malic acid salt) of Compound 1. The malic acid salt form ofCompound 1 is referred to herein as “Compound 1 malate salt,” “Compound1 L-malate salt,” “Compound 1 malic acid salt form,” “Compound 1 malicacid,” “Compound 1 malate,” or “Compound 1 L-malate.” An alternativename for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidemalate.

In some embodiments, the salt of the invention is a camphorsulfonic acidsalt of Compound 1. The camphorsulfonic acid salt form of Compound 1 isreferred to herein as “Compound 1 camsylate salt,” “Compound 1camphorsulfonic acid salt form,” “Compound 1 (1S)-(+)-10-camphorsulfonicacid,” “Compound 1 camphorsulfonic acid,” or “Compound 1 camsylate.” Analternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidecamsylate.

In some embodiments, the salt of the invention is a mandelic acid saltof Compound 1. The mandelic acid salt form of Compound 1 is referred toherein as “Compound 1 mandelate salt,” “Compound 1 mandelic acid saltform,” “Compound 1 mandelic acid,” “Compound 1 (5)-(+)-mandelic acid,”“Compound 1 mandelate,” or “Compound 1 (S)-(+)-mandelate.” Analternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidemandelate.

In some embodiments, the salt of the invention is a citric acid salt ofCompound 1. The citric acid salt form of Compound 1 is referred toherein as “Compound 1 citrate salt,” “Compound 1 citric acid salt form,”“Compound 1 citric acid,” or “Compound 1 citrate.” An alternative namefor the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidecitrate.

The present invention is directed to, inter alia, solid forms ofN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Compound 2) and salts thereof, the structure of which is shown below.

Compound 2 is described in U.S. patert application Ser. No. 16/278,865(published as US Patert Publication No. 2019/0382380), the entirety ofwhich is incorporated herein by reference.

Compound 2 and its salts can be isolated as one or more solid forms. Thesolid forms (e.g., crystalline forms) described herein have manyadvantages, for example they have desirable properties, such as ease ofhandling, ease of processing, storage stability, and ease ofpurification. Moreover, the crystalline forms can be useful forimproving the performance characteristics of a pharmaceutical productsuch as dissolution profile, shelf-life and bioavailability. Forexample, the phosphoric acid salt of Compound 2 (e.g., the dihydratephosphoric acid salt of Compound 2) is advantageous because it is highlycrystalline, isolable as a single polymorph, non-hygroscopic, stable inaqueous formulations, and can be made reproducibly.

In some embodiments, the salt of Compound 2 is an acid salt of Compound2. In some embodiments, the acid is selected from phosphoric acid andhydrochloric acid.

In some embodiments, the salt of the invention is a phosphoric acid saltof Compound 2. The phosphoric acid salt form of Compound 2 is referredto herein as “Compound 2 phosphate salt,” “Compound 2 phosphoric acidsalt form,” “Compound 2 phosphoric acid,” or “Compound 2 phosphate.” Analternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidephosphate.

In some embodiments, the salt of the invention is a hydrochloric acidsalt of Compound 2. The hydrochloric acid salt form of Compound 2 isreferred to herein as “Compound 2 hydrochloride salt,” “Compound 2hydrochloric acid salt form,” “Compound 2 hydrochloric acid,” or“Compound 2 hydrochloride.” An alternative name for the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidehydrochloride.

The salts of the invention can be isolated as one or more solid forms.As used herein, the phrase “solid form” refers to a salt of theinvention in either an amorphous state or a crystalline state(“crystalline form” or “crystalline solid”), whereby a salt of theinvention in a crystalline state may optionally include solvent or waterwithin the crystalline lattice, for example, to form a solvated orhydrated crystalline form. In some embodiments, the salt of the presentinvention is in a crystalline state as described herein. The term“hydrated,” as used herein, is meant to refer to a crystalline form thatincludes one or more water molecules in the crystalline lattice. Example“hydrated” crystalline forms include hemihydrates, monohydrates,dihydrates, and the like. Other hydrated forms such as channel hydratesand the like are also included within the meaning of the term.

In some embodiments, salts of the invention can be prepared by anysuitable method for the preparation of acid addition salts. For example,the free base of a compound (e.g., Compound 1 or Compound 2) can becombined with the desired acid in a solvent or in a melt. Alternatively,an acid addition salt of a compound can be converted to a different acidaddition salt by anion exchange. Salts of the invention which areprepared in a solvent system can be isolated by precipitation from thesolvent. Precipitation and/or crystallization can be induced, forexample, by evaporation, reduction of temperature, addition ofanti-solvent, or combinations thereof.

In some embodiments, the salts of the invention are crystalline,including crystalline forms which are anhydrous, hydrated, non-solvated,or solvated. Example hydrates include hemihydrates, monohydrates,dihydrates, and the like. In some embodiments, the crystalline salts areanhydrous and non-solvated. By “anhydrous” is meant that the crystallinesalt contains no bound water in the crystal lattice structure, i.e., thecompound does not form a crystalline hydrate.

In some embodiments, the salts of the invention are substantiallyisolated. By “substantially isolated” is meant that the salt is at leastpartially or substantially separated from the environment in which itwas formed or detected. Partial separation can include, for example, acomposition enriched in the salt of the invention. Substantialseparation can include compositions containing at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, at least about 95%, at least about 97%, or at least about 99% byweight of the salt.

The salt forms of the invention were found to be highly crystalline, adesirable property which can facilitate, for example, purification ofthe drug such as by crystallization and recrystallization as necessary.Further, a crystalline form tends to be more stable and can be easier tomill or micronize when formulating a drug. Crystalline salts also tendhave excellent properties with respect to solubility and can be moresuitable to be manufactured reproducibly in a clear acid/base ratio,facilitating the preparation of liquid formulations for oral as well asfor intravenous applications.

As used herein, the term “crystalline” or “crystalline form” refers to acrystalline solid form of a chemical compound, including, but notlimited to, a single-component or multiple-component crystal form, e.g.,including solvates, hydrates, clathrates, and a co-crystals. As usedherein, “crystalline form” is meant to refer to a certain latticeconfiguration of a crystalline substance. Different crystalline forms ofthe same substance typically have different crystalline lattices (e.g.,unit cells) which are attributed to different physical properties thatare characteristic of each of the crystalline forms. In some instances,different lattice configurations have different water or solventcontert. The different crystalline lattices can be identified by solidstate characterization methods such as by X-ray powder diffraction(XRPD). Other characterization methods such as differential scanningcalorimetry (DSC), thermogravimetric analysis (TGA), dynamic vaporsorption (DVS), solid state NMR, and the like further help identify thecrystalline form as well as help determine stability and solvent/watercontert.

Crystalline forms of a substance include both solvated (e.g., hydrated)and non-solvated (e.g., anhydrous) forms. A hydrated form is acrystalline form that includes water in the crystalline lattice.Hydrated forms can be stoichiometric hydrates, where the water ispresent in the lattice in a certain water/molecule ratio such as forhemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also benon-stoichiometric, where the water contert is variable and dependent onexternal conditions such as humidity.

As used herein, the term “substantially crystalline,” means a majorityof the weight of a sample or preparation of a salt (or hydrate orsolvate thereof) of the invention is crystalline and the remainder ofthe sample is a non-crystalline form (e.g., amorphous form) of the samecompound. In some embodiments, a substantially crystalline sample has atleast about 95% crystallinity (e.g., about 5% of the non-crystallineform of the same compound), preferably at least about 96% crystallinity(e.g., about 4% of the non-crystalline form of the same compound), morepreferably at least about 97% crystallinity (e.g., about 3% of thenon-crystalline form of the same compound), even more preferably atleast about 98% crystallinity (e.g., about 2% of the non-crystallineform of the same compound), still more preferably at least about 99%crystallinity (e.g., about 1% of the non-crystalline form of the samecompound), and most preferably about 100% crystallinity (e.g., about 0%of the non-crystalline form of the same compound). In some embodiments,the term “fully crystalline” means at least about 99% or about 100%crystallinity.

Crystalline forms are most commonly characterized by XRPD. An XRPDpattern of reflections (peaks) is typically considered a fingerprint ofa particular crystalline form. It is well known that the relativeintensities of the XRPD peaks can widely vary depending on, inter alfa,the sample preparation technique, crystal size distribution, filters,the sample mounting procedure, and the particular instrument employed.In some instances, new peaks may be observed or existing peaks maydisappear, depending on the type of instrument or the settings (forexample, whether a Ni filter is used or not). As used herein, the term“peak” refers to a reflection having a relative height/intensity of atleast about 4% of the maximum peak height/intensity. Moreover,instrument variation and other factors can affect the 2-theta values.Thus, peak assignments, such as those reported herein, can vary by plusor minus about 0.2° (2-theta), and the term “substantially” as used inthe context of XRPD herein is meant to encompass the above-mentionedvariations.

In the same way, temperature readings in connection with DSC, TGA, orother thermal experiments can vary about ±3° C. depending on theinstrument, particular settings, sample preparation, etc. For example,with DSC it is known that the temperatures observed will depend on therate of the temperature change as well as the sample preparationtechnique and the particular instrument employed. Thus, the valuesreported herein related to DSC thermograms can vary, as indicated above,by ±3° C. Accordingly, a crystalline form reported herein having a DSCthermogram “substantially” as shown in any of the Figures is understoodto accommodate such variation.

The salts and compounds disclosed herein can include all isotopes ofatoms occurring within them. Isotopes include those atoms having thesame atomic number but different mass numbers. For example, isotopes ofhydrogen include tritium and deuterium. Salts and compounds of theinvention can also include all isotopes of atoms occurring in theintermediates or final compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. For example, isotopesof hydrogen include tritium and deuterium. One or more constituent atomsof the compounds of the invention can be replaced or substituted withisotopes of the atoms in natural or non-natural abundance. In someembodiments, the compound includes at least one deuterium atom. Forexample, one or more hydrogen atoms in a compound of the presentdisclosure can be replaced or substituted by deuterium. In someembodiments, the compound includes two or more deuterium atoms. In someembodiments, the compound includes 1, 2, 3, 4, 5, 6, 7 or 8 deuteriumatoms. Synthetic methods for including isotopes into organic compoundsare known in the art.

As used herein, and unless otherwise specified, the term “about”, whenused in connection with a numeric value or range of values which isprovided to describe a particular solid form (e.g., a specifictemperature or temperature range, such as describing a melting,dehydration, or glass transition; a mass change, such as a mass changeas a function of temperature or humidity; a solvent or water contert, interms of, for example, mass or a percentage; or a peak position, such asin analysis by, for example, ¹³C NMR, DSC, TGA and XRPD), indicate thatthe value or range of values may deviate to an extert deemed reasonableto one of ordinary skill in the art while still describing theparticular solid form. Specifically, the term “about”, when used in thiscontext, indicates that the numeric value or range of values may vary by5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2% or0.1% of the recited value or range of values while still describing theparticular solid form. The term “about”, when used in reference to adegree 2-theta value refers to +/−0.2 degrees 2-theta.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, the term “melting point” refers to an endothermic eventor endothermal event observed in e.g., a DSC experiment. An endothermicevent is a process or reaction in which a sample absorbs energy from itssurrounding in the form of e.g., heat as in a DSC experiment. Anexothermic event is a process or reaction in which a sample releasesenergy. The process of heat absorption and release can be detected byDSC. In some embodiments, the term “melting point” is used to describethe major endothermic event revealed on a particular DSC thermogram.

The term “room temperature” as used herein, is understood in the art,and refers generally to a temperature, e.g., a reaction temperature,that is about the temperature of the room in which the reaction iscarried out, for example, a temperature from about 20° C. to about 30°C. The term “elevated temperature” as used herein, is understood in theart, and refer generally to a temperature, e.g., a reaction temperature,that is above room temperature, e.g., above 30° C.

Solid Forms of Compound 1 Compound 1 Form I

Provided herein is a solid form of Compound 1 which is crystalline,referred to as Form I, which is described below in the Examples.

Provided herein are also processes for preparing Form I of Compound 1comprising recrystallizing Compound 1 in a solvent. In some embodiments,the solvent is a polar solvent. In some embodiments, the solvent is C₁₋₆alkyl alcohol solvent. In some embodiments, the solvent is isopropylalcohol.

In some embodiments, Form I has at least one characteristic XRPD peakselected from about 6.7, about 9.9, about 13.4, and about 15.5 degrees2-theta. In some embodiments, Form I has at least two characteristicXRPD peaks selected from about 6.7, about 9.9, about 13.4, and about15.5 degrees 2-theta. In some embodiments, Form I has at least threecharacteristic XRPD peaks selected from about 6.7, about 9.9, about13.4, and about 15.5 degrees 2-theta. In some embodiments, Form I has aXRPD peak at about 6.7 degrees 2-theta. In some embodiments, Form I hasa XRPD peak at about 9.9 degrees 2-theta. In some embodiments, Form Ihas a XRPD peak at about 13.4 degrees 2-theta. In some embodiments, FormI has a XRPD peak at about 15.5 degrees 2-theta.

In some embodiments, Form I has at least one characteristic XRPD peakselected from about 6.7, about 9.9, about 13.4, about 14.1, about 15.5,about 18.3, about 19.9, and about 20.4 degrees 2-theta. In someembodiments, Form I has at least two characteristic XRPD peaks selectedfrom about 6.7, about 9.9, about 13.4, about 14.1, about 15.5, about18.3, about 19.9, and about 20.4 degrees 2-theta. In some embodiments,Form I has at least three characteristic XRPD peaks selected from about6.7, about 9.9, about 13.4, about 14.1, about 15.5, about 18.3, about19.9, and about 20.4 degrees 2-theta.

In some embodiments, Form I has at least one characteristic XRPD peakselected from about 6.7, about 9.9, about 13.4, about 14.1, about 14.6,about 15.5, about 18.3, about 19.9, about 20.4, about 21.0, about 22.8,and about 25.5 degrees 2-theta. In some embodiments, Form I has at leasttwo characteristic XRPD peaks selected from about 6.7, about 9.9, about13.4, about 14.1, about 14.6, about 15.5, about 18.3, about 19.9, about20.4, about 21.0, about 22.8, and about 25.5 degrees 2-theta. In someembodiments, Form I has at least three characteristic XRPD peaksselected from about 6.7, about 9.9, about 13.4, about 14.1, about 14.6,about 15.5, about 18.3, about 19.9, about 20.4, about 21.0, about 22.8,and about 25.5 degrees 2-theta.

In some embodiments, Form I has an XRPD pattern with characteristicpeaks as substantially shown in FIG. 1.

In some embodiments, Form I exhibits a DSC thermogram having endothermpeaks at temperatures of about 86° C. and about 183° C. In someembodiments, Form I exhibits a DSC thermogram having an endotherm peakat a temperature of about 86° C. In some embodiments, Form I exhibits aDSC thermogram having an endotherm peak at a temperature of about 183°C. In some embodiments, Form I has a DSC thermogram substantially asdepicted in FIG. 2. In some embodiments, Form I has a TGA thermogramsubstantially as depicted in FIG. 3.

In some embodiments, Form I has at least one characteristic XRPD peakselected from about 6.7, about 9.9, about 13.4, and about 15.5 degrees2-theta; and Form I exhibits a DSC thermogram having endotherm peaks attemperatures of about 86° C. and about 183° C. In some embodiments, FormI has at least one characteristic XRPD peak selected from about 6.7,about 9.9, about 13.4, and about 15.5 degrees 2-theta; and Form Iexhibits a DSC thermogram having an endotherm peak at a temperatures ofabout 86° C. In some embodiments, Form I has at least one characteristicXRPD peak selected from about 6.7, about 9.9, about 13.4, and about 15.5degrees 2-theta; and Form I exhibits a DSC thermogram having anendotherm peak at a temperatures of about 183° C.

In some embodiments, Form I can be isolated with a purity of at leastabout 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, or about 99%. In some embodiments, Form I can be isolated with apurity greater than about 99%.

Phosphoric Acid Salts

The phosphoric acid salt of Compound 1 can be prepared by any suitablemethod for preparation of phosphoric acid addition salts. For example,Compound 1 can be combined with phosphoric acid (e.g., about 1.0 molareq or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In certain embodiments, Compound 1 iscombined with about 1 to about 2 molar equivalents of phosphoric acid.In certain embodiments, Compound 1 is combined with about 1 to about 1.5molar equivalents of phosphoric acid. In certain embodiments, Compound 1is combined with about 1.05 molar equivalents of phosphoric acid. Insome embodiments, the solvent is a polar solvent. In some embodiments,the solvent is a C₁₋₆ alkyl alcohol. In some embodiments, the solvent ismethanol.

The phosphoric acid salt of Compound 1 can be crystallized to provide acrystalline solid form. In some embodiments, the crystallization of thephosphoric acid salt of Compound 1 comprises precipitating thephosphoric acid salt of Compound 1 from a crystallizing solvent. In someembodiments, the crystallizing solvent is a polar solvent. In someembodiments, the crystallizing solvent is water.

In some embodiments, the phosphoric acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 6.4, about 7.0, about11.2, and about 12.5 degrees 2-theta. In some embodiments, thephosphoric acid salt of Compound 1 has at least two characteristic XRPDpeaks selected from about 6.4, about 7.0, about 11.2, and about 12.5degrees 2-theta. In some embodiments, the phosphoric acid salt ofCompound 1 has at least three characteristic XRPD peaks selected fromabout 6.4, about 7.0, about 11.2, and about 12.5 degrees 2-theta. Insome embodiments, the phosphoric acid salt of Compound 1 has acharacteristic XRPD peak at about 6.4 degrees 2-theta. In someembodiments, the phosphoric acid salt of Compound 1 has a characteristicXRPD peak at about 7.0 degrees 2-theta. In some embodiments, thephosphoric acid salt of Compound 1 has a characteristic XRPD peak atabout 11.2 degrees 2-theta. In some embodiments, the phosphoric acidsalt of Compound 1 has a characteristic XRPD peak at about 12.5 degrees2-theta.

In some embodiments, the phosphoric acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 6.3, about 6.4, about7.0, about 8.9, about 11.2, about 12.5, about 19.9, and about 22.9degrees 2-theta. In some embodiments, the phosphoric acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 6.3, about 6.4, about 7.0, about 8.9, about 11.2, about 12.5,about 19.9, and about 22.9 degrees 2-theta. In some embodiments, thephosphoric acid salt of Compound 1 has at least three characteristicXRPD peaks selected from about 6.3, about 6.4, about 7.0, about 8.9,about 11.2, about 12.5, about 19.9, and about 22.9 degrees 2-theta.

In some embodiments, the phosphoric acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 6.3, about 6.4, about7.0, about 8.9, about 11.2, about 12.5, about 15.8, about 17.0, about18.0, about 19.9, about 22.9, about 24.5, and about 25.2 degrees2-theta. In some embodiments, the phosphoric acid salt of Compound 1 hasat least two characteristic XRPD peaks selected from about 6.3, about6.4, about 7.0, about 8.9, about 11.2, about 12.5, about 15.8, about17.0, about 18.0, about 19.9, about 22.9, about 24.5, and about 25.2degrees 2-theta. In some embodiments, the phosphoric acid salt ofCompound 1 has at least three characteristic XRPD peaks selected fromabout 6.3, about 6.4, about 7.0, about 8.9, about 11.2, about 12.5,about 15.8, about 17.0, about 18.0, about 19.9, about 22.9, about 24.5,and about 25.2 degrees 2-theta.

In some embodiments, the phosphoric acid salt of Compound 1 has an XRPDpattern with characteristic peaks as substantially shown in FIG. 4.

In some embodiments, the phosphoric acid salt of Compound 1 exhibits aDSC thermogram having endothermic peaks at temperatures of about 92° C.and about 229° C. In some embodiments, the phosphoric acid salt ofCompound 1 exhibits a DSC thermogram having an endothermic peak at atemperature of about 92° C. In some embodiments, the phosphoric acidsalt of Compound 1 exhibits a DSC thermogram having an endothermic peakat a temperature of about 229° C. In some embodiments, the phosphoricacid salt of Compound 1 has a DSC thermogram substantially as depictedin FIG. 5. In some embodiments, the phosphoric acid salt of Compound 1has a TGA thermogram substantially as depicted in FIG. 6.

In some embodiments, the phosphoric acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 6.4, about 7.0, about11.2, and about 12.5 degrees 2-theta; and the phosphoric acid saltexhibits a DSC thermogram having endothermic peaks at temperatures ofabout 92° C. and about 229° C. In some embodiments, the phosphoric acidsalt of Compound 1 has at least one characteristic XRPD peak selectedfrom about 6.4, about 7.0, about 11.2, and about 12.5 degrees 2-theta;and the phosphoric acid salt exhibits a DSC thermogram having anendothermic peak at a temperature of about 92° C. In some embodiments,the phosphoric acid salt of Compound 1 has at least one characteristicXRPD peak selected from about 6.4, about 7.0, about 11.2, and about 12.5degrees 2-theta; and the phosphoric acid salt exhibits a DSC thermogramhaving an endothermic peak at a temperature of about 229° C.

In some embodiments, the phosphoric acid salt of Compound 1 issubstantially crystalline. In some embodiments, the salt is crystalline.

Hydrochloric Acid Salts

The hydrochloric acid salt of Compound 1 can be prepared by any suitablemethod for preparation of hydrochloric acid addition salts. For example,Compound 1 can be combined with hydrochloric acid (e.g., about 1.0 molareq or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In certain embodiments, Compound 1 iscombined with about 1 to about 2 molar equivalents of hydrochloric acid.In certain embodiments, Compound 1 is combined with about 1 to about 1.5molar equivalents of hydrochloric acid. In certain embodiments, Compound1 is combined with about 1.05 molar equivalents of hydrochloric acid. Insome embodiments, the solvent is a polar solvent. In some embodiments,the solvent is a Ch6 alkyl alcohol. In some embodiments, the solvent ismethanol.

The hydrochloric acid salt of Compound 1 can be crystallized to providea crystalline solid form. In some embodiments, the crystallization ofthe hydrochloric acid salt of Compound 1 comprises precipitating thehydrochloric acid salt of Compound 1 from a crystallizing solvent. Insome embodiments, the crystallizing solvent is a polar solvent. In someembodiments, the crystallizing solvent is water.

In some embodiments, the hydrochloric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 6.7, about 9.1,about 13.5, and about 15.5 degrees 2-theta. In some embodiments, thehydrochloric acid salt of Compound 1 has at least two characteristicXRPD peaks selected from about 6.7, about 9.1, about 13.5, and about15.5 degrees 2-theta. In some embodiments, the hydrochloric acid salt ofCompound 1 has at least three characteristic XRPD peaks selected fromabout 6.7, about 9.1, about 13.5, and about 15.5 degrees 2-theta. Insome embodiments, the hydrochloric acid salt of Compound 1 has acharacteristic XRPD peak at about 6.7 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 1 has acharacteristic XRPD peak at about 9.1 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 1 has acharacteristic XRPD peak at about 13.5 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 1 has acharacteristic XRPD peak at about 15.5 degrees 2-theta.

In some embodiments, the hydrochloric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 6.7, about 9.1,about 11.0, about 12.7, about 13.5, about 15.5, about 17.1, and about23.4 degrees 2-theta. In some embodiments, the hydrochloric acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 6.7, about 9.1, about 11.0, about 12.7, about 13.5, about 15.5,about 17.1, and about 23.4 degrees 2-theta. In some embodiments, thehydrochloric acid salt of Compound 1 has at least three characteristicXRPD peaks selected from about 6.7, about 9.1, about 11.0, about 12.7,about 13.5, about 15.5, about 17.1, and about 23.4 degrees 2-theta.

In some embodiments, the hydrochloric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.5, about 6.0,about 6.7, about 9.1, about 10.6, about 11.0, about 12.7, about 13.5,about 15.5, about 17.1, about 18.2, about 21.2, about 22.7, and about23.4 degrees 2-theta. In some embodiments, the hydrochloric acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 4.5, about 6.0, about 6.7, about 9.1, about 10.6, about 11.0,about 12.7, about 13.5, about 15.5, about 17.1, about 18.2, about 21.2,about 22.7, and about 23.4 degrees 2-theta. In some embodiments, thehydrochloric acid salt of Compound 1 has at least three characteristicXRPD peaks selected from about 4.5, about 6.0, about 6.7, about 9.1,about 10.6, about 11.0, about 12.7, about 13.5, about 15.5, about 17.1,about 18.2, about 21.2, about 22.7, and about 23.4 degrees 2-theta.

In some embodiments, the hydrochloric acid salt of Compound 1 has anXRPD pattern with characteristic peaks as substantially shown in FIG. 7.

In some embodiments, the hydrochloric acid salt of Compound 1 exhibits aDSC thermogram having endothermic peaks at temperatures of about 107° C.and about 233° C. In some embodiments, the hydrochloric acid salt ofCompound 1 exhibits a DSC thermogram having an endothermic peak at atemperature of about 107° C. In some embodiments, the hydrochloric acidsalt of Compound 1 exhibits a DSC thermogram having an endothermic peakat a temperature of about 233° C. In some embodiments, the hydrochloricacid salt of Compound 1 has a DSC thermogram substantially as depictedin FIG. 8. In some embodiments, the hydrochloric acid salt h of Compound1 as a TGA thermogram substantially as depicted in FIG. 9.

In some embodiments, the hydrochloric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 6.7, about 9.1,about 13.5, and about 15.5 degrees 2-theta; and the hydrochloric acidsalt exhibits a DSC thermogram having endothermic peaks at temperaturesof about 107° C. and about 233° C. In some embodiments, the hydrochloricacid salt of Compound 1 has at least one characteristic XRPD peakselected from about 6.7, about 9.1, about 13.5, and about 15.5 degrees2-theta; and the hydrochloric acid salt exhibits a DSC thermogram havingan endothermic peak at a temperature of about 107° C. In someembodiments, the hydrochloric acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 6.7, about 9.1, about 13.5,and about 15.5 degrees 2-theta; and the hydrochloric acid salt exhibitsa DSC thermogram having an endothermic peak at a temperature of about233° C.

In some embodiments, the hydrochloric acid salt of Compound 1 issubstantially crystalline. In some embodiments, the salt is crystalline.

L-(+)-Tartaric Acid Salts

The L-(+)-tartaric acid salt of Compound 1 can be prepared by anysuitable method for preparation of L-(+)-tartaric acid addition salts.For example, Compound 1 can be combined with L-(+)-tartaric acid (e.g.,about 1.0 molar eq or more) in a solvent and the resulting salt can beisolated by filtering the salt from solution. In certain embodiments,Compound 1 is combined with about 1 to about 2 molar equivalents ofL-(+)-tartaric acid. In certain embodiments, Compound 1 is combined withabout 1 to about 1.5 molar equivalents of L-(+)-tartaric acid. Incertain embodiments, Compound 1 is combined with about 1.15 molarequivalents of L-(+)-tartaric acid. In some embodiments, the solvent isa polar solvent. In some embodiments, the solvent is a C₁₋₆ alkylalcohol. In some embodiments, the solvent is methanol.

The L-(+)-tartaric acid salt of Compound 1 can be crystallized toprovide a crystalline solid form. In some embodiments, thecrystallization of the L-(+)-tartaric acid salt of Compound 1 comprisesprecipitating the L-(+)-tartaric acid salt of Compound 1 from acrystallizing solvent. In some embodiments, the crystallizing solvent isa polar solvent. In some embodiments, the crystallizing solvent iswater.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 7.9,and about 9.8 degrees 2-theta. In some embodiments, the L-(+)-tartaricacid salt of Compound 1 has at least two characteristic XRPD peaksselected from about 4.9, about 7.9, and about 9.8 degrees 2-theta. Insome embodiments, the L-(+)-tartaric acid salt of Compound 1 has threecharacteristic XRPD peaks selected from about 4.9, about 7.9, and about9.8 degrees 2-theta. In some embodiments, the L-(+)-tartaric acid saltof Compound 1 has a characteristic XRPD peak at about 4.9 degrees2-theta. In some embodiments, the L-(+)-tartaric acid salt of Compound 1has a characteristic XRPD peak at about 7.9 degrees 2-theta. In someembodiments, the L-(+)-tartaric acid salt of Compound 1 has acharacteristic XRPD peak at about 9.8 degrees 2-theta.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 7.9,about 9.8, about 15.9, about 16.9, about 19.6, and about 23.0 degrees2-theta. In some embodiments, the L-(+)-tartaric acid salt of Compound 1has at least two characteristic XRPD peaks selected from about 4.9,about 7.9, about 9.8, about 15.9, about 16.9, about 19.6, and about 23.0degrees 2-theta. In some embodiments, the L-(+)-tartaric acid salt ofCompound 1 has at least three characteristic XRPD peaks selected fromabout 4.9, about 7.9, about 9.8, about 15.9, about 16.9, about 19.6, andabout 23.0 degrees 2-theta.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 7.5,about 7.9, about 9.8, about 10.5, about 13.7, about 14.7, about 15.9,about 16.0, about 16.9, about 18.1, about 19.6, about 20.8, about 23.0,and about 24.7 degrees 2-theta. In some embodiments, the L-(+)-tartaricacid salt of Compound 1 has at least two characteristic XRPD peaksselected from about 4.9, about 7.5, about 7.9, about 9.8, about 10.5,about 13.7, about 14.7, about 15.9, about 16.0, about 16.9, about 18.1,about 19.6, about 20.8, about 23.0, and about 24.7 degrees 2-theta. Insome embodiments, the L-(+)-tartaric acid salt of Compound 1 has atleast three characteristic XRPD peaks selected from about 4.9, about7.5, about 7.9, about 9.8, about 10.5, about 13.7, about 14.7, about15.9, about 16.0, about 16.9, about 18.1, about 19.6, about 20.8, about23.0, and about 24.7 degrees 2-theta.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 has anXRPD pattern with characteristic peaks as substantially shown in FIG.10.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 exhibitsa DSC thermogram having endothermic peaks at temperatures of about 102°C. and about 217° C. In some embodiments, the endothermic peak is at atemperature of about 102° C. In some embodiments, the endothermic peakis at a temperature of about 217° C. In some embodiments, theL-(+)-tartaric acid salt of Compound 1 has a DSC thermogramsubstantially as depicted in FIG. 11. In some embodiments, theL-(+)-tartaric acid salt of Compound 1 has a TGA thermogramsubstantially as depicted in FIG. 12.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 7.9,and about 9.8 degrees 2-theta; and the L-(+)-tartaric acid salt exhibitsa DSC thermogram having endothermic peaks at temperatures of about 102°C. and about 217° C. In some embodiments, the L-(+)-tartaric acid saltof Compound 1 has at least one characteristic XRPD peak selected fromabout 4.9, about 7.9, and about 9.8 degrees 2-theta; and theL-(+)-tartaric acid salt exhibits a DSC thermogram having an endothermicpeak at a temperature of about 102° C. In some embodiments, theL-(+)-tartaric acid salt of Compound 1 has at least one characteristicXRPD peak selected from about 4.9, about 7.9, and about 9.8 degrees2-theta; and the L-(+)-tartaric acid salt exhibits a DSC thermogramhaving an endothermic peak at a temperature of about 217° C.

In some embodiments, the L-(+)-tartaric acid salt of Compound 1 issubstantially crystalline. In some embodiments, the salt is crystalline.

Malic Acid Salts

The malic acid salt of Compound 1 can be prepared by any suitable methodfor preparation of malic acid addition salts. For example, Compound 1can be combined with L-(−)-malic acid (e.g., about 1.0 molar eq or more)in a solvent and the resulting salt can be isolated by filtering thesalt from solution. In certain embodiments, Compound 1 is combined withabout 1 to about 2 molar equivalents of L-(−)-malic acid. In certainembodiments, Compound 1 is combined with about 1 to about 1.5 molarequivalents of L-(-)-malic acid. In certain embodiments, Compound 1 iscombined with about 1.2 molar equivalents of L-(-)-malic acid. In someembodiments, the solvent is a polar solvent. In some embodiments, thesolvent is a C₁₋₆ alkyl alcohol. In some embodiments, the solvent ismethanol.

The malic acid salt of Compound 1 can be crystallized to provide acrystalline solid form. In some embodiments, the crystallization of themalic acid salt of Compound 1 comprises precipitating the malic acidsalt of Compound 1 from a crystallizing solvent. In some embodiments,the crystallizing solvent is a polar solvent. In some embodiments, thesolvent is a C₁₋₆ alkyl alcohol. In some embodiments, the solvent ismethanol.

In some embodiments, the malic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 5.2, about 10.4, and about21.0 degrees 2-theta. In some embodiments, the malic acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 5.2, about 10.4, and about 21.0 degrees 2-theta. In someembodiments, the malic acid salt of Compound 1 has three characteristicXRPD peaks selected from about 5.2, about 10.4, and about 21.0 degrees2-theta. In some embodiments, the malic acid salt of Compound 1 has acharacteristic XRPD peak at about 5.2 degrees 2-theta. In someembodiments, the malic acid salt of Compound 1 has a characteristic XRPDpeak at about 10.4 degrees 2-theta. In some embodiments, the malic acidsalt of Compound 1 has a characteristic XRPD peak at about 21.0 degrees2-theta.

In some embodiments, the malic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 5.2, about 7.9, about 10.4,about 14.3, about 15.8, about 16.6, about 18.0, about 21.0, and about21.2 degrees 2-theta. In some embodiments, the malic acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 5.2, about 7.9, about 10.4, about 14.3, about 15.8, about 16.6,about 18.0, about 21.0, and about 21.2 degrees 2-theta. In someembodiments, the malic acid salt of Compound 1 has at least threecharacteristic XRPD peaks selected from about 5.2, about 7.9, about10.4, about 14.3, about 15.8, about 16.6, about 18.0, about 21.0, andabout 21.2 degrees 2-theta.

In some embodiments, the malic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 5.2, about 7.9, about 8.2,about 10.4, about 14.3, about 15.8, about 16.6, about 18.0, about 19.2,about 21.0, about 21.2, about 25.9 degrees 2-theta. In some embodiments,the malic acid salt of Compound 1 has at least two characteristic XRPDpeaks selected from about 5.2, about 7.9, about 8.2, about 10.4, about14.3, about 15.8, about 16.6, about 18.0, about 19.2, about 21.0, about21.2, about 25.9 degrees 2-theta. In some embodiments, the malic acidsalt of Compound 1 has at least three characteristic XRPD peaks selectedfrom about 5.2, about 7.9, about 8.2, about 10.4, about 14.3, about15.8, about 16.6, about 18.0, about 19.2, about 21.0, about 21.2, about25.9 degrees 2-theta.

In some embodiments, the malic acid salt of Compound 1 has an XRPDpattern with characteristic peaks as substantially shown in FIG. 13.

In some embodiments, the malic acid salt of Compound 1 exhibits a DSCthermogram having endothermic peaks at temperatures of about 71° C. andabout 198° C. In some embodiments, the malic acid salt of Compound 1exhibits a DSC thermogram having an endothermic peak at a temperature ofabout 71° C. In some embodiments, the malic acid salt of Compound 1exhibits a DSC thermogram having an endothermic peak at a temperature ofabout 198° C. In some embodiments, the malic acid salt of Compound 1 hasa DSC thermogram substantially as depicted in FIG. 14. In someembodiments, the malic acid salt of Compound 1 has a TGA thermogramsubstantially as depicted in FIG. 15.

In some embodiments, the malic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 5.2, about 10.4, and about21.0 degrees 2-theta; and the malic acid salt exhibits a DSC thermogramhaving endothermic peaks at temperatures of about 71° C. and about 198°C. In some embodiments, the malic acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 5.2, about 10.4, andabout 21.0 degrees 2-theta; and the malic acid salt exhibits a DSCthermogram having an endothermic peak at a temperature of about 71° C.In some embodiments, the malic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 5.2, about 10.4, and about21.0 degrees 2-theta;

and the malic acid salt exhibits a DSC thermogram having an endothermicpeak at a temperature of about 198° C.

In some embodiments, the malic acid salt of Compound 1 is substantiallycrystalline. In some embodiments, the salt is crystalline.

Camphorsulfonic Acid Salts

The camphorsulfonic acid salt of Compound 1 can be prepared by anysuitable method for preparation of camphorsulfonic acid addition salts.For example, Compound 1 can be combined with (1S)-(+)-camphorsulfonicacid (e.g., about 1.0 molar eq or more) in a solvent and the resultingsalt can be isolated by filtering the salt from solution. In certainembodiments, Compound 1 is combined with about 1 to about 2 molarequivalents of (1S)-(+)-camphorsulfonic acid. In certain embodiments,Compound 1 is combined with about 1 to about 1.5 molar equivalents of(1S)-(+)-camphorsulfonic acid. In certain embodiments, Compound 1 iscombined with about 1.1 molar equivalents of (1S)-(+)-camphorsulfonicacid. In some embodiments, the solvent is a polar solvent. In someembodiments, the solvent is a C₁₋₆ alkyl alcohol. In some embodiments,the solvent is methanol.

The camphorsulfonic acid salt of Compound 1 can be crystallized toprovide a crystalline solid form. In some embodiments, thecrystallization of the camphorsulfonic acid salt of Compound 1 comprisesprecipitating the camphorsulfonic acid salt of Compound 1 from acrystallizing solvent. In some embodiments, the crystallizing solvent isa polar solvent. In some embodiments, the solvent is water.

In some embodiments, the camphorsulfonic acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 5.9,and about 15.1 degrees 2-theta. In some embodiments, the camphorsulfonicacid salt of Compound 1 has at least two characteristic XRPD peaksselected from about 4.9, about 5.9, and about 15.1 degrees 2-theta. Insome embodiments, the camphorsulfonic acid salt of Compound 1 has threecharacteristic XRPD peaks selected from about 4.9, about 5.9, and about15.1 degrees 2-theta. In some embodiments, the camphorsulfonic acid saltof Compound 1 has a characteristic XRPD peak at about 4.9 degrees2-theta. In some embodiments, the camphorsulfonic acid salt of Compound1 has a characteristic XRPD peak at about 5.9 degrees 2-theta. In someembodiments, the camphorsulfonic acid salt of Compound 1 has acharacteristic XRPD peak at about 15.1 degrees 2-theta.

In some embodiments, the camphorsulfonic acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 5.9,about 10.9, about 14.4, about 15.0, about 15.1, about 19.8, about 20.1,and about 25.8 degrees 2-theta. In some embodiments, the camphorsulfonicacid salt of Compound 1 has at least two characteristic XRPD peaksselected from about 4.9, about 5.9, about 10.9, about 14.4, about 15.0,about 15.1, about 19.8, about 20.1, and about 25.8 degrees 2-theta. Insome embodiments, the camphorsulfonic acid salt of Compound 1 has atleast three characteristic XRPD peaks selected from about 4.9, about5.9, about 10.9, about 14.4, about 15.0, about 15.1, about 19.8, about20.1, and about 25.8 degrees 2-theta.

In some embodiments, the camphorsulfonic acid salt of Compound 1 has atleast one characteristic XRPD peak selected about 4.9, about 5.9, about9.8, about 10.9, about 12.2, about 14.4, about 15.0, about 15.1, about16.5, about 19.8, about 20.1, about 20.9, and about 25.8 degrees2-theta. In some embodiments, the camphorsulfonic acid salt of Compound1 has at least two characteristic XRPD peaks selected from about 4.9,about 5.9, about 9.8, about 10.9, about 12.2, about 14.4, about 15.0,about 15.1, about 16.5, about 19.8, about 20.1, about 20.9, and about25.8 degrees 2-theta. In some embodiments, the camphorsulfonic acid saltof Compound 1 has at least three characteristic XRPD peaks selected fromabout 4.9, about 5.9, about 9.8, about 10.9, about 12.2, about 14.4,about 15.0, about 15.1, about 16.5, about 19.8, about 20.1, about 20.9,and about 25.8 degrees 2-theta.

In some embodiments, the camphorsulfonic acid salt of Compound 1 has anXRPD pattern with characteristic peaks as substantially shown in FIG.16.

In some embodiments, the camphorsulfonic acid salt of Compound 1exhibits a DSC thermogram having endothermic peaks at temperatures ofabout 64° C. and about 236° C. In some embodiments, the camphorsulfonicacid salt of Compound 1 exhibits a DSC thermogram having an endothermicpeak at a temperature of about 64° C. In some embodiments, thecamphorsulfonic acid salt of Compound 1 exhibits a DSC thermogram havingan endothermic peak at a temperature of about 236° C. In someembodiments, the camphorsulfonic acid salt of Compound 1 has a DSCthermogram substantially as depicted in FIG. 17. In some embodiments,the camphorsulfonic acid salt of Compound 1 has a TGA thermogramsubstantially as depicted in FIG. 18.

In some embodiments, the camphorsulfonic acid salt of Compound 1 has atleast one characteristic XRPD peak selected from about 4.9, about 5.9,and about 15.1 degrees 2-theta; and the camphorsulfonic acid saltexhibits a DSC thermogram having endothermic peaks at temperatures ofabout 64° C. and about 236° C. In some embodiments, the camphorsulfonicacid salt of Compound 1 has at least one characteristic XRPD peakselected from about 4.9, about 5.9, and about 15.1 degrees 2-theta; andthe camphorsulfonic acid salt exhibits a DSC thermogram having anendothermic peak at a temperature of about 64° C. In some embodiments,the camphorsulfonic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 4.9, about 5.9, and about15.1 degrees 2-theta; and the camphorsulfonic acid salt exhibits a DSCthermogram having an endothermic peak at a temperature of about 236° C.

In some embodiments, the camphorsulfonic acid salt of Compound 1 issubstantially crystalline. In some embodiments, the salt is crystalline.

Mandelic Acid Salts

The mandelic acid salt of Compound 1 can be prepared by any suitablemethod for preparation of mandelic acid addition salts. For example,Compound 1 can be combined with (S)-(+)-mandelic acid (e.g., about 1.0molar eq or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In certain embodiments, Compound 1 iscombined with about 1 to about 2 molar equivalents of (S)-(+)-mandelicacid. In certain embodiments, Compound 1 is combined with about 1 toabout 1.5 molar equivalents of (S)-(+)-mandelic acid. In certainembodiments, Compound 1 is combined with about 1.2 molar equivalents of(S)-(+)-mandelic acid. In some embodiments, the solvent is a polarsolvent. In some embodiments, the solvent is a C1_6 alkyl alcohol. Insome embodiments, the solvent is methanol.

The mandelic acid salt of Compound 1 can be crystallized to provide acrystalline solid form. In some embodiments, the crystallization of themandelic acid salt of Compound 1 comprises precipitating the mandelicacid salt of Compound 1 from a crystallizing solvent. In someembodiments, the crystallizing solvent is a polar solvent. In someembodiments, the solvent is water.

In some embodiments, the mandelic acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 4.2, about 5.0, about5.8, and about 6.9 degrees 2-theta. In some embodiments, the mandelicacid salt of Compound 1 has at least two characteristic XRPD peaksselected from about 4.2, about 5.0, about 5.8, and about 6.9 degrees2-theta. In some embodiments, the mandelic acid salt of Compound 1 hasat least three characteristic XRPD peaks selected from about 4.2, about5.0, about 5.8, and about 6.9 degrees 2-theta. In some embodiments, themandelic acid salt of Compound 1 has a characteristic XRPD peak at about4.2 degrees 2-theta. In some embodiments, the mandelic acid salt ofCompound 1 has a characteristic XRPD peak at about 5.0 degrees 2-theta.In some embodiments, the mandelic acid salt of Compound 1 has acharacteristic XRPD peak at about 5.8 degrees 2-theta. In someembodiments, the mandelic acid salt of Compound 1 has a characteristicXRPD peak at about 6.9 degrees 2-theta.

In some embodiments, the mandelic acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 4.2, about 5.0, about5.4, about 5.8, about 6.9, about 14.2, about 15.3, about 19.0, and about19.6 degrees 2-theta. In some embodiments, the mandelic acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 4.2, about 5.0, about 5.4, about 5.8, about 6.9, about 14.2, about15.3, about 19.0, and about 19.6 degrees 2-theta. In some embodiments,the mandelic acid salt of Compound 1 has at least three characteristicXRPD peaks selected from about 4.2, about 5.0, about 5.4, about 5.8,about 6.9, about 14.2, about 15.3, about 19.0, and about 19.6 degrees2-theta.

In some embodiments, the mandelic acid salt of Compound 1 has at leastone characteristic XRPD peak selected about 4.2, about 5.0, about 5.4,about 5.8, about 6.9, about 10.1, about 12.6, about 14.2, about 15.0,about 15.3, about 17.1, about 18.7, about 19.0, and about 19.6 degrees2-theta. In some embodiments, the mandelic acid salt of Compound 1 hasat least two characteristic XRPD peaks selected from about 4.2, about5.0, about 5.4, about 5.8, about 6.9, about 10.1, about 12.6, about14.2, about 15.0, about 15.3, about 17.1, about 18.7, about 19.0, andabout 19.6 degrees 2-theta. In some embodiments, the mandelic acid saltof Compound 1 has at least three characteristic XRPD peaks selected fromabout 4.2, about 5.0, about 5.4, about 5.8, about 6.9, about 10.1, about12.6, about 14.2, about 15.0, about 15.3, about 17.1, about 18.7, about19.0, and about 19.6 degrees 2-theta.

In some embodiments, the mandelic acid salt of Compound 1 has an XRPDpattern with characteristic peaks as substantially shown in FIG. 19.

In some embodiments, the mandelic acid salt of Compound 1 exhibits a DSCthermogram having endothermic peaks at temperatures of about 93° C. andabout 217° C. In some embodiments, the mandelic acid salt of Compound 1exhibits a DSC thermogram having an endothermic peak at a temperature ofabout 93° C. In some embodiments, the mandelic acid salt of Compound 1exhibits a DSC thermogram having an endothermic peak at a temperature ofabout 217° C. In some embodiments, the mandelic acid salt of Compound 1has a DSC thermogram substantially as depicted in FIG. 20. In someembodiments, the mandelic acid salt of Compound 1 has a TGA thermogramsubstantially as depicted in FIG. 21.

In some embodiments, the mandelic acid salt of Compound 1 has at leastone characteristic XRPD peak selected from about 4.2, about 5.0, about5.8, and about 6.9 degrees 2-theta; and the mandelic acid salt exhibitsa DSC thermogram having endothermic peaks at temperatures of about 93°C. and about 217° C. In some embodiments, the mandelic acid salt ofCompound 1 has at least one characteristic XRPD peak selected from about4.2, about 5.0, about 5.8, and about 6.9 degrees 2-theta; and themandelic acid salt exhibits a DSC thermogram having an endothermic peakat a temperature of about 93° C. In some embodiments, the mandelic acidsalt of Compound 1 has at least one characteristic XRPD peak selectedfrom about 4.2, about 5.0, about 5.8, and about 6.9 degrees 2-theta; andthe mandelic acid salt exhibits a DSC thermogram having an endothermicpeak at a temperature of about 217° C.

In some embodiments, the mandelic acid salt of Compound 1 issubstantially crystalline. In some embodiments, the salt is crystalline.

Citric Acid Salts

The citric acid salt of Compound 1 can be prepared by any suitablemethod for preparation of citric acid addition salts. For example,Compound 1 can be combined with citric acid (e.g., about 1.0 molar eq ormore) in a solvent and the resulting salt can be isolated by filteringthe salt from solution. In certain embodiments, Compound 1 is combinedwith about 1 to about 2 molar equivalents of citric acid. In certainembodiments, Compound 1 is combined with about 1 to about 1.5 molarequivalents of citric acid. In certain embodiments, Compound 1 iscombined with about 1.05 molar equivalents of citric acid. In someembodiments, the solvent is a polar solvent. In some embodiments, thesolvent is a C₁₋₆ alkyl alcohol. In some embodiments, the solvent isacetone. In some embodiments, the solvent is a mixture of acetone andwater.

The citric acid salt of Compound 1 can be crystallized to provide acrystalline solid form. In some embodiments, the crystallization of thecitric acid salt of Compound 1 comprises precipitating the citric acidsalt of Compound 1 from a crystallizing solvent. In some embodiments,the crystallizing solvent is acetone. In some embodiments, thecrystallizing solvent is a mixture of acetone and water.

In some embodiments, the citric acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 7.3, about 9.0, about 13.6,and about 18.3 degrees 2-theta. In some embodiments, the citric acidsalt of Compound 1 has at least two characteristic XRPD peaks selectedfrom about 7.3, about 9.0, about 13.6, and about 18.3 degrees 2-theta.In some embodiments, the citric acid salt of Compound 1 has at leastthree characteristic XRPD peaks selected from about 7.3, about 9.0,about 13.6, and about 18.3 degrees 2-theta. In some embodiments, thecitric acid salt of Compound 1 has a characteristic XRPD peak at about7.3 degrees 2-theta. In some embodiments, the citric acid salt ofCompound 1 has a characteristic XRPD peak at about 9.0 degrees 2-theta.In some embodiments, the citric acid salt of Compound 1 has acharacteristic XRPD peak at about 13.6 degrees 2-theta. In someembodiments, the citric acid salt of Compound 1 has a characteristicXRPD peak at about 18.3 degrees 2-theta.

In some embodiments, the citric acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 7.3, about 9.0, about 13.6,about 16.6, about 18.1, about 18.3, about 19.5, about 20.1, and about20.9 degrees 2-theta. In some embodiments, the citric acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 7.3, about 9.0, about 13.6, about 16.6, about 18.1, about 18.3,about 19.5, about 20.1, and about 20.9 degrees 2-theta. In someembodiments, the citric acid salt of Compound 1 has at least threecharacteristic XRPD peaks selected from about 7.3, about 9.0, about13.6, about 16.6, about 18.1, about 18.3, about 19.5, about 20.1, andabout 20.9 degrees 2-theta.

In some embodiments, the citric acid salt of Compound 1 has at least onecharacteristic XRPD peak selected about 7.3, about 9.0, about 13.6,about 13.9, about 14.9, about 16.6, about 18.1, about 18.3, about 18.8,about 19.5, about 20.1, about 20.9, about 21.6, about 22.4, and about24.5 degrees 2-theta. In some embodiments, the citric acid salt ofCompound 1 has at least two characteristic XRPD peaks selected fromabout 7.3, about 9.0, about 13.6, about 13.9, about 14.9, about 16.6,about 18.1, about 18.3, about 18.8, about 19.5, about 20.1, about 20.9,about 21.6, about 22.4, and about 24.5 degrees 2-theta. In someembodiments, the citric acid salt of Compound 1 has at least threecharacteristic XRPD peaks selected from about 7.3, about 9.0, about13.6, about 13.9, about 14.9, about 16.6, about 18.1, about 18.3, about18.8, about 19.5, about 20.1, about 20.9, about 21.6, about 22.4, andabout 24.5 degrees 2-theta.

In some embodiments, the citric acid salt of Compound 1 has an XRPDpattern with characteristic peaks as substantially shown in FIG. 22.

In some embodiments, the citric acid salt of Compound 1 exhibits a DSCthermogram having an endothermic peak at temperatures of about 210° C.In some embodiments, the citric acid salt of Compound 1 has a DSCthermogram substantially as depicted in FIG. 23. In some embodiments,the citric acid salt of Compound 1 has a TGA thermogram substantially asdepicted in FIG. 24.

In some embodiments, the citric acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 7.3, about 9.0, about 13.6,and about 18.3 degrees 2-theta; and the citric acid salt exhibits a DSCthermogram having an endothermic peak at a temperature of about 210° C.

In some embodiments, the citric acid salt of Compound 1 is substantiallycrystalline. In some embodiments, the salt is crystalline.

Solid Forms of Compound 2 Phosphoric Acid Salts

The phosphoric acid salt of Compound 2 can be prepared by any suitablemethod for preparation of phosphoric acid addition salts. For example,Compound 2 can be combined with phosphoric acid (e.g., about 1.0 molareq or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In certain embodiments, Compound 2 iscombined with about 1 to about 2 molar equivalents of phosphoric acid.In certain embodiments, Compound 2 is combined with about 1 to about 1.5molar equivalents of phosphoric acid. In certain embodiments, Compound 2is combined with about 1.05 molar equivalents of phosphoric acid. Insome embodiments, the solvent is a polar solvent. In some embodiments,the solvent is acetone.

The phosphoric acid salt of Compound 2 can be crystallized to provide acrystalline solid form. In some embodiments, the crystallization of thephosphoric acid salt of Compound 2 comprises precipitating thephosphoric acid salt of Compound 2 from a crystallizing solvent. In someembodiments, the crystallizing solvent is acetone.

In some embodiments, the phosphoric acid salt of Compound 2 has at leastone characteristic XRPD peak selected from about 6.7, about 10.2, about14.5, and about 18.0 degrees 2-theta. In some embodiments, thephosphoric acid salt of Compound 2 has at least two characteristic XRPDpeaks selected from about 6.7, about 10.2, about 14.5, and about 18.0degrees 2-theta. In some embodiments, the phosphoric acid salt ofCompound 2 has at least three characteristic XRPD peaks selected fromabout 6.7, about 10.2, about 14.5, and about 18.0 degrees 2-theta. Insome embodiments, the phosphoric acid salt of Compound 2 has acharacteristic XRPD peak at about 6.7 degrees 2-theta. In someembodiments, the phosphoric acid salt of Compound 2 has a characteristicXRPD peak at about 10.2 degrees 2-theta. In some embodiments, thephosphoric acid salt of Compound 2 has a characteristic XRPD peak atabout 14.5 degrees 2-theta. In some embodiments, the phosphoric acidsalt of Compound 2 has a characteristic XRPD peak at about 18.0 degrees2-theta.

In some embodiments, the phosphoric acid salt of Compound 2 has at leastone characteristic XRPD peak selected from about 5.9, about 6.7, about10.2, about 13.4, about 14.5, about 15.5, about 16.5, about 17.4, andabout 18.0 degrees 2-theta. In some embodiments, the phosphoric acidsalt of Compound 2 has at least two characteristic XRPD peaks selectedfrom about 5.9, about 6.7, about 10.2, about 13.4, about 14.5, about15.5, about 16.5, about 17.4, and about 18.0 degrees 2-theta. In someembodiments, the phosphoric acid salt of Compound 2 has at least threecharacteristic XRPD peaks selected from about 5.9, about 6.7, about10.2, about 13.4, about 14.5, about 15.5, about 16.5, about 17.4, andabout 18.0 degrees 2-theta.

In some embodiments, the phosphoric acid salt of Compound 2 has at leastone characteristic XRPD peak selected from about 5.9, about 6.3, about6.7, about 10.2, about 11.0, about 11.9, about 13.4, about 14.5, about15.5, about 15.9, about 16.5, about 17.4, about 18.0, about 19.2, about20.4, and about 23.3 degrees 2-theta. In some embodiments, thephosphoric acid salt of Compound 2 has at least two characteristic XRPDpeaks selected from about 5.9, about 6.3, about 6.7, about 10.2, about11.0, about 11.9, about 13.4, about 14.5, about 15.5, about 15.9, about16.5, about 17.4, about 18.0, about 19.2, about 20.4, and about 23.3degrees 2-theta. In some embodiments, the phosphoric acid salt ofCompound 2 has at least three characteristic XRPD peaks selected fromabout 5.9, about 6.3, about 6.7, about 10.2, about 11.0, about 11.9,about 13.4, about 14.5, about 15.5, about 15.9, about 16.5, about 17.4,about 18.0, about 19.2, about 20.4, and about 23.3 degrees 2-theta.

In some embodiments, phosphoric acid salt of Compound 2 has an XRPDpattern with characteristic peaks as substantially shown in FIG. 25.

In some embodiments, the phosphoric acid salt of Compound 2 exhibits aDSC thermogram having endothermic peaks at temperatures of about 116° C.and about 200° C. In some embodiments, the phosphoric acid salt ofCompound 2 exhibits a DSC thermogram having an endothermic peak at atemperature of about 116° C. In some embodiments, the phosphoric acidsalt of Compound 2 exhibits a DSC thermogram having an endothermic peakat a temperature of about 200° C. In some embodiments, the phosphoricacid salt of Compound 2 has a DSC thermogram substantially as depictedin FIG. 26. In some embodiments, the phosphoric acid salt of Compound 2has a TGA thermogram substantially as depicted in FIG. 27.

In some embodiments, the phosphoric acid salt of Compound 2 has at leastone characteristic XRPD peak selected from about 6.7, about 10.2, about14.5, and about 18.0 degrees 2-theta; and the phosphoric acid salt ofCompound 2 exhibits a DSC thermogram having endothermic peaks attemperatures of about 116° C. and about 200° C. In some embodiments, thephosphoric acid salt of Compound 2 has at least one characteristic XRPDpeak selected from about 6.7, about 10.2, about 14.5, and about 18.0degrees 2-theta; and the phosphoric acid salt of Compound 2 exhibits aDSC thermogram having an endothermic peak at a temperature of about 116°C. In some embodiments, the phosphoric acid salt of Compound 2 has atleast one characteristic XRPD peak selected from about 6.7, about 10.2,about 14.5, and about 18.0 degrees 2-theta; and the phosphoric acid saltof Compound 2 exhibits a DSC thermogram having an endothermic peak at atemperature of about 200° C.

In some embodiments, the phosphoric acid salt of Compound 2 issubstantially crystalline. In some embodiments, the salt is crystalline.In some embodiments, the salt is a hydrate. In certain embodiments, thesalt is a dihydrate.

Hydrochloric Acid Salts

The hydrochloric acid salt of Compound 2 can be prepared by any suitablemethod for preparation of hydrochloric acid addition salts. For example,Compound 2 can be combined with hydrochloric acid (e.g., about 1.0 molareq or more) in a solvent and the resulting salt can be isolated byfiltering the salt from solution. In certain embodiments, Compound 2 iscombined with about 1 to about 2 molar equivalents of hydrochloric acid.In certain embodiments, Compound 2 is combined with about 1 to about 1.5molar equivalents of hydrochloric acid. In certain embodiments, Compound2 is combined with about 1.05 molar equivalents of hydrochloric acid. Insome embodiments, the solvent is a polar solvent. In some embodiments,the solvent is a Ch6 alkyl alcohol. In some embodiments, the solvent ismethanol.

The hydrochloric acid salt of Compound 2 can be crystallized to providea crystalline solid form. In some embodiments, the crystallization ofthe hydrochloric acid salt of Compound 2 comprises precipitating thehydrochloric acid salt of Compound 1 from a crystallizing solvent. Insome embodiments, the crystallizing solvent is a polar solvent. In someembodiments, the crystallizing solvent is a Ch6 alkyl alcohol. In someembodiments, the crystallizing solvent is methanol.

In some embodiments, the hydrochloric acid salt of Compound 2 has atleast one characteristic XRPD peak selected from about 6.2, about 6.8,about 11.2, and about 17.3 degrees 2-theta. In some embodiments, thehydrochloric acid salt of Compound 2 has at least two characteristicXRPD peaks selected from about 6.2, about 6.8, about 11.2, and about17.3 degrees 2-theta. In some embodiments, the hydrochloric acid salt ofCompound 2 has at least three characteristic XRPD peaks selected fromabout 6.2, about 6.8, about 11.2, and about 17.3 degrees 2-theta. Insome embodiments, the hydrochloric acid salt of Compound 2 has acharacteristic XRPD peak at about 6.2 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 2 has acharacteristic XRPD peak at about 6.8 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 2 has acharacteristic XRPD peak at about 11.2 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 2 has acharacteristic XRPD peak at about 17.3 degrees 2-theta.

In some embodiments, the hydrochloric acid salt of Compound 2 has atleast one characteristic XRPD peak selected from about 6.2, about 6.8,about 11.2, about 12.5, about 13.6, about 17.3, about 18.4, about 21.6,and about 22.3 degrees 2-theta. In some embodiments, the hydrochloricacid salt of Compound 2 has at least two characteristic XRPD peaksselected from about 6.2, about 6.8, about 11.2, about 12.5, about 13.6,about 17.3, about 18.4, about 21.6, and about 22.3 degrees 2-theta. Insome embodiments, the hydrochloric acid salt of Compound 2 has at leastthree characteristic XRPD peaks selected from about 6.2, about 6.8,about 11.2, about 12.5, about 13.6, about 17.3, about 18.4, about 21.6,and about 22.3 degrees 2-theta.

In some embodiments, the hydrochloric acid salt of Compound 2 has atleast one characteristic XRPD peak selected from about 6.2, about 6.8,about 11.2, about 12.5, about 13.6, about 13.8, about 16.8, about 17.3,about 18.4, about 21.6, about 22.3, and about 24.1 degrees 2-theta. Insome embodiments, the hydrochloric acid salt of Compound 2 has at leasttwo characteristic XRPD peaks selected from about 6.2, about 6.8, about11.2, about 12.5, about 13.6, about 13.8, about 16.8, about 17.3, about18.4, about 21.6, about 22.3, and about 24.1 degrees 2-theta. In someembodiments, the hydrochloric acid salt of Compound 2 has at least threecharacteristic XRPD peaks selected from about 6.2, about 6.8, about11.2, about 12.5, about 13.6, about 13.8, about 16.8, about 17.3, about18.4, about 21.6, about 22.3, and about 24.1 degrees 2-theta.

In some embodiments, the hydrochloric salt of Compound 2 has an XRPDpattern with characteristic peaks as substantially shown in FIG. 28.

In some embodiments, the hydrochloric acid salt of Compound 2 exhibits aDSC thermogram having endothermic peaks at temperatures of about 130° C.and about 249° C. In some embodiments, the hydrochloric acid salt ofCompound 2 exhibits a DSC thermogram having an endothermic peak at atemperature of about 130° C. In some embodiments, the hydrochloric acidsalt of Compound 2 exhibits a DSC thermogram having an endothermic peakat a temperature of about 249° C. In some embodiments, the hydrochloricacid salt of Compound 2 has a DSC thermogram substantially as depictedin FIG. 29. In some embodiments, the hydrochloric acid salt of Compound2 has a TGA thermogram substantially as depicted in FIG. 30.

In some embodiments, the hydrochloric acid salt of Compound 2 has atleast one characteristic XRPD peak selected from about 6.2, about 6.8,about 11.2, and about 17.3 degrees 2-theta; and the hydrochloric acidsalt of Compound 2 exhibits a DSC thermogram having endothermic peaks attemperatures of about 130° C. and about 249° C. In some embodiments, thehydrochloric acid salt of Compound 2 has at least one characteristicXRPD peak selected from about 6.2, about 6.8, about 11.2, and about 17.3degrees 2-theta; and the hydrochloric acid salt of Compound 2 exhibits aDSC thermogram having an endothermic peak at a temperature of about 130°C. In some embodiments, the hydrochloric acid salt of Compound 2 has atleast one characteristic XRPD peak selected from about 6.2, about 6.8,about 11.2, and about 17.3 degrees 2-theta; and the hydrochloric acidsalt of Compound 2 exhibits a DSC thermogram having an endothermic peakat a temperature of about 249° C.

In some embodiments, the hydrochloric acid salt of Compound 2 issubstantially crystalline. In some embodiments, the salt is crystalline.

Methods of Use

Studies have established that HPK1 is a negative regulator of T cell andB cell activation (Hu, M. C., et al., Genes Dev, 1996. 10(18): p.2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p. 7013-25).HPK1-deficient mouse T cells showed dramatically increased activation ofTCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potertially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-α etc),and demonstrated superior ability to stimulate T cell proliferation invitro and in vivo as compared to wild-type DCs (Alzabin, S., et al., JImmunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 isalso an important negative regulator of dendritic cell activation(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). However,the signaling mechanisms underlying HPK-1 mediated negative regulationof DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188(supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188(supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, by contacting HPK1 with a compound of the invention, or asolid form or salt thereof. In some embodiments, the contacting can beadministering to a patient a compound provided herein, or a or a solidform or salt thereof. In certain embodiments, the compounds of thepresent disclosure, or a solid form or salt thereof, are useful fortherapeutic administration to enhance, stimulate and/or increaseimmunity in cancer. For example, a method of treating a disease ordisorder associated with inhibition of HPK1 interaction can includeadministering to a patient in need thereof a therapeutically effectiveamount of a compound provided herein, or a solid form or salt thereof.The compounds of the present disclosure, or a solid form or saltthereof, can be used alone, in combination with other agents ortherapies or as an adjuvant or neoadjuvant for the treatment of diseasesor disorders, including cancers. For the uses described herein, any ofthe compounds of the disclosure, or a solid form or salt thereof,including any of the embodiments thereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure, or solid forms or salts thereof include, but are notlimited to, bone cancer, pancreatic cancer, skin cancer, cancer of thehead or neck, cutaneous or intraocular malignant melanoma, uterinecancer, ovarian cancer, rectal cancer, cancer of the anal region,stomach cancer, testicular cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, endometrial cancer,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, chronic or acute leukemias including acutemyeloid leukemia, chronic myeloid leukemia, acute lymphoblasticleukemia, chronic lymphocytic leukemia, solid tumors of childhood,lymphocytic lymphoma, cancer of the bladder, cancer of the kidney orurethra, carcinoma of the renal pelvis, neoplasm of the central nervoussystem (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axistumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma,epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure, or solid forms or salts thereof, include melanoma (e.g.,metastatic malignant melanoma), renal cancer (e.g. clear cellcarcinoma), prostate cancer (e.g. hormone refractory prostateadenocarcinoma), breast cancer, triple-negative breast cancer, coloncancer and lung cancer (e.g. non-small cell lung cancer and small celllung cancer). Additionally, the disclosure includes refractory orrecurrent malignancies whose growth may be inhibited using the compoundsof the disclosure, or solid forms or salts thereof.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure, or solid forms or salts thereof, include, butare not limited to, solid tumors (e.g., prostate cancer, colon cancer,esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer,renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breastcancer, lung cancer, cancers of the head and neck, thyroid cancer,glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers(e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL),acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma,Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrentfollicular), Hodgkin lymphoma or multiple myeloma) and combinations ofsaid cancers.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure, or solid forms or saltsthereof, include but are not limited to hematological cancers, sarcomas,lung cancers, gastrointestinal cancers, genitourinary tract cancers,liver cancers, bone cancers, nervous system cancers, gynecologicalcancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre -tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

As used herein, the term “contacting” refers to the bringing together ofthe indicated moieties in an in vitro system or an in vivo system suchthat they are in sufficient physical proximity to interact.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention, or solid forms orsalts thereof, are useful in preventing or reducing the risk ofdeveloping any of the diseases referred to herein; e.g., preventing orreducing the risk of developing a disease, condition or disorder in anindividual who may be predisposed to the disease, condition or disorderbut does not yet experience or display the pathology or symptomatologyof the disease.

Combination Therapies

I. Immune-Checkpoint Therapies

In some embodiments, the compounds provided herein, or solid forms orsalts thereof, can be used in combination with one or more immunecheckpoint inhibitors for the treatment of cancer as described herein.Compounds of the present disclosure, or solid forms or salts thereof,can be used in combination with one or more immune checkpointinhibitors. Exemplary immune checkpoint inhibitors include inhibitorsagainst immune checkpoint molecules such as CD20, CD28, CD39, CD40,CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM,arginase, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4,LAG3, TIM3, VISTA, TIGIT, PD-1, PD-Ll and PD-L2. In some embodiments,the immune checkpoint molecule is a stimulatory checkpoint moleculeselected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In someembodiments, the immune checkpoint molecule is an inhibitory checkpointmolecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3,PD-1, TIM3, TIGIT, and VISTA. In some embodiments, the compounds of thedisclosure provided herein, or solid forms or salts thereof, can be usedin combination with one or more agents selected from KIR inhibitors,TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors andTGFR beta inhibitors.

In some embodiments, the compounds provided herein, or solid forms orsalts thereof, can be used in combination with one or more agonists ofimmune checkpoint molecules, e.g., OX40, CD27, GITR, and CD137 (alsoknown as 4-1BB).

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), durvalumab (Imfinzi®),pidilizumab, SHR-1210, PDR001, MGA012, PDR001, AB122, or AMP-224. Insome embodiments, the anti-PD-1 monoclonal antibody is nivolumab orpembrolizumab. In some embodiments, the anti-PD1 antibody ispembrolizumab. In some embodiments, the anti-PD-1 monoclonal antibody isMGA012. In some embodiments, the anti-PD1 antibody is SHR-1210. Otheranti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g.urelumab, utomilumab).

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1 and PD-L1, e.g., an anti-PD-1/PD-L1 monoclonalantibody. In some embodiments, the anti-PD-1/PD-L1 is MCLA-136.

In some embodiments, the inhibitor is MCLA-145.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CSF1R, e.g., an anti- CSF1R antibody. In someembodiments, the anti- CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, IMP321, GSK2831781, orINCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MEDI1873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is INCAGN01949, MEDI0562,MEDI6469, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178. In someembodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with bispecific antibodies. In someembodiments, one of the domains of the bispecific antibody targets PD-1,PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3 or TGFβreceptor.

In some embodiments, the compounds of the disclosure, or solid forms orsalts thereof, can be used in combination with one or more metabolicenzyme inhibitors. In some embodiments, the metabolic enzyme inhibitoris an inhibitor of IDO 1, TDO, or arginase. Examples of IDOL inhibitorsinclude epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099and LY338196. An example of an arginase inhibitor is CB-1158.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

II. Cancer Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Examples of agents that may be combined with compounds ofthe present disclosure, or solid forms or salts thereof, includeinhibitors of the PI3K-AKT-mTOR pathway, inhibitors of the Raf-MAPKpathway, inhibitors of JAK-STAT pathway, inhibitors of beta cateninpathway, inhibitors of notch pathway, inhibitors of hedgehog pathway,inhibitors of Pim kinases, and inhibitors of protein chaperones and cellcycle progression. Targeting more than one signaling pathway (or morethan one biological molecule involved in a given signaling pathway) mayreduce the likelihood of drug-resistance arising in a cell population,and/or reduce the toxicity of treatment.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with one or more otherenzyme/protein/receptor inhibitors for the treatment of diseases, suchas cancer. Examples of cancers include solid tumors and liquid tumors,such as blood cancers. For example, the compounds of the presentdisclosure, or solid forms or salts thereof, can be combined with one ormore inhibitors of the following kinases for the treatment of cancer:Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylasekinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R,IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1,FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3,VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn,Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In someembodiments, the compounds of the present disclosure, or solid forms orsalts thereof, can be combined with one or more of the followinginhibitors for the treatment of cancer. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure, or solid forms or salts thereof, for treatment of cancersinclude an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., AZD4547,BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib,TAS-120, JNJ-42756493, Debio1347, INCB54828, INCB62079 and INCB63904), aJAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib orINCB39110), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1inhibitor (e.g., GSK2979552, INCB59872 and INCB60003), a TDO inhibitor,a PI3K-delta inhibitor (e.g., INCB50797 and INCB50465), a PI3K-gammainhibitor such as a PI3K-gamma selective inhibitor, a CSF1R inhibitor(e.g., PLX3397 and LY3022855), a TAM receptor tyrosine kinases (Tyro-3,Axl, and Mer), an angiogenesis inhibitor, an interleukin receptorinhibitor, bromo and extra terminal family members inhibitors (forexample, bromodomain inhibitors or BET inhibitors such as OTX015,CPI-0610, INCB54329 and INCB57643) and an adenosine receptor antagonistor combinations thereof. Inhibitors of HDAC such as panobinostat andvorinostat. Inhibitors of c-Met such as onartumzumab, tivantnib, andINC-280. Inhibitors of BTK such as ibrutinib. Inhibitors of mTOR such asrapamycin, sirolimus, temsirolimus, and everolimus. Inhibitors of Raf,such as vemurafenib and dabrafenib. Inhibitors of MEK such astrametinib, selumetinib and GDC-0973. Inhibitors of Hsp90 (e.g.,tanespimycin), cyclin dependent kinases (e.g., palbociclib), PARP (e.g.,olaparib) and Pim kinases (LGH447, INCB053914 and SGI-1776) can also becombined with compounds of the present disclosure.

Compounds of the present disclosure, or solid forms or salts thereof,can be used in combination with one or more agents for the treatment ofdiseases such as cancer. In some embodiments, the agent is an alkylatingagent, a proteasome inhibitor, a corticosteroid, or an immunomodulatoryagent. Examples of an alkylating agent include bendamustine, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes, uracil mustard, chlormethine, cyclophosphamide (Cytoxan™),ifosfamide, melphalan, chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfilzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure, or solid forms or saltsthereof, can further be used in combination with other methods oftreating cancers, for example by chemotherapy, irradiation therapy,tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery.Examples of immunotherapy include cytokine treatment (e.g., interferons,GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonalantibody, adoptive T cell transfer, CAR (Chimeric antigen receptor) Tcell treatment as a booster for T cell activation, oncolytic virotherapyand immunomodulating small molecules, including thalidomide or JAK1/2inhibitor and the like. The compounds can be administered in combinationwith one or more anti-cancer drugs, such as a chemotherapeutics. Examplechemotherapeutics include any of: abarelix, abiraterone, afatinib,aflibercept, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, amsacrine, anastrozole, aphidicolon, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone, camptosar,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,epothilones, erlotinib, estramustine, etoposide phosphate, etoposide,exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine,fluorouracil, flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumabozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan,idarubicin, idelalisib, ifosfamide, imatinib mesylate, interferon alfa2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole,leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, porfimer, prednisone, procarbazine, quinacrine, ranibizumab,rasburicase, regorafenib, reloxafine, revlimid, rituximab, ruxolitinib,sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen,tegafur, temozolomide, teniposide, testolactone, thalidomide,thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab,tretinoin, triptorelin, uracil mustard, valrubicin, vandetanib,vinblastine, vincristine, vindesine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure, or solid forms or saltsthereof, can further be used in combination with one or moreanti-inflammatory agents, steroids, immunosuppressants or therapeuticantibodies. The steroids include but are not limited to 17alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone,fluoxymesterone, methylprednisolone, methyltestosterone, prednisolone,triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide,and medroxyprogesteroneacetate.

The compounds of the present disclosure, or solid forms or saltsthereof, can also be used in combination with lonafarnib (SCH6636),tipifarnib (R115777), L778123, BMS 214662, tezacitabine (MDL 101731),Smll, triapine, didox, trimidox and amidox.

The compounds of the disclosure, or salts or solid forms thereof, can becombined with another immunogenic agent, such as cancerous cells,purified tumor antigens (including recombinant proteins, peptides, andcarbohydrate molecules), cells, and cells transfected with genesencoding immune stimulating cytokines. Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with a vaccination protocol for thetreatment of cancer. In some embodiments, the tumor cells are transducedto express GM-CSF. In some embodiments, tumor vaccines include theproteins from viruses implicated in human cancers such as HumanPapilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi'sHerpes Sarcoma Virus (KHSV). In some embodiments, the compounds of thepresent disclosure, or solid forms or salts thereof, can be used incombination with tumor specific antigen such as heat shock proteinsisolated from tumor tissue itself. In some embodiments, the compounds ofthe present disclosure, or solid forms or salts thereof, can be combinedwith dendritic cells immunization to activate potert anti-tumorresponses.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with bispecific macrocyclic peptidesthat target Fe alpha or Fe gamma receptor-expressing effectors cells totumor cells. The compounds of the present disclosure, or solid forms orsalts thereof, can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure, or solid forms or saltsthereof, can be used in combination with bone marrow transplant for thetreatment of a variety of tumors of hematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

In some embodiments, the compounds of the present disclosure, or solidforms or salts thereof, can be used in combination with INCB086550.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure, or solid forms or salts thereof, can be administered in theform of pharmaceutical compositions. Thus the present disclosureprovides a composition comprising the compounds of the presentdisclosure, or solid forms or salts thereof, and at least onepharmaceutically acceptable carrier or excipient. These compositions canbe prepared in a manner well known in the pharmaceutical art, and can beadministered by a variety of routes, depending upon whether local orsystemic treatment is indicated and upon the area to be treated.Administration may be topical (including transdermal, epidermal,ophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal orintranasal), oral or parenteral. Parenteral administration includesintravenous, intraarterial, subcutaneous, intraperitoneal intramuscularor injection or infusion; or intracranial, e.g., intrathecal orintraventricular, administration. Parenteral administration can be inthe form of a single bolus dose, or may be, e.g., by a continuousperfusion pump. Pharmaceutical compositions and formulations for topicaladministration may include transdermal patches, ointments, lotions,creams, gels, drops, suppositories, sprays, liquids and powders.Conventional pharmaceutical carriers, aqueous, powder or oily bases,thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient the compounds of the present disclosure, orsolid forms or salts thereof, in combination with one or morepharmaceutically acceptable carriers or excipients. In some embodiments,the composition is suitable for topical administration. In making thecompositions of the invention, the active ingredient is typically mixedwith an excipient, diluted by an excipient or enclosed within such acarrier in the form of, e.g., a capsule, sachet, paper, or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols (as a solid or in aliquid medium), ointments containing, e.g., up to 10% by weight of theactive compound, soft and hard gelatin capsules, suppositories, sterileinjectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the present disclosure, or solid forms or saltsthereof, may be milled using known milling procedures such as wetmilling to obtain a particle size appropriate for tablet formation andfor other formulation types. Finely divided (nanoparticulate)preparations of the compounds of the invention can be prepared byprocesses known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising a compound of the present disclosure, or a solid form or saltthereof, and at least one pharmaceutically acceptable carrier orexcipient. In some embodiments, the composition comprises at least onecompound described herein, or a pharmaceutically acceptable saltthereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potertially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention, or asolid form or salt thereof, can vary according to, e.g., the particularuse for which the treatment is made, the manner of administration of thecompound, the health and condition of the patient, and the judgment ofthe prescribing physician. The proportion or concentration of a compoundof the disclosure in a pharmaceutical composition can vary dependingupon a number of factors including dosage, chemical characteristics(e.g., hydrophobicity), and the route of administration. For example,the compounds of the invention or a salt or solid form thereof, can beprovided in an aqueous physiological buffer solution containing about0.1 to about 10% w/v of the compound for parenteral administration. Sometypical dose ranges are from about 1 □g/kg to about 1 g/kg of bodyweight per day. In some embodiments, the dose range is from about 0.01mg/kg to about 100 mg/kg of body weight per day. The dosage is likely todepend on such variables as the type and extert of progression of thedisease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected,formulation of the excipient, and its route of administration. Effectivedoses can be extrapolated from dose-response curves derived from invitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tert, or intermittert positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention, or asolid form or salt thereof, can vary according to, e.g., the particularuse for which the treatment is made, the manner of administration of thecompound, the health and condition of the patient, and the judgment ofthe prescribing physician. The proportion or concentration of a compoundof the invention, or a solid form or salt thereof, in a pharmaceuticalcomposition can vary depending upon a number of factors includingdosage, chemical characteristics (e.g., hydrophobicity), and the routeof administration. For example, the compounds of the invention, or solidforms or salts thereof, can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extert of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

EXAMPLES Experimental Methods

In the below examples, X-Ray Powder Diffraction analysis was carried outon a Bruker D8 Advance ECO X-ray Powder Diffractometer (XRPD)instrument. The general experimental procedures for XRPD were: (1) X-rayradiation from copper at 1.5418 Å and LYNXEYE™ detector; (2) X-ray powerat 40 kV, 25 mA; and (3) the sample powder was dispersed on azero-background sample holder. The general measurement conditions forXRPD were: Start Angle 3 degrees; Stop Angle 30 degrees; Sampling 0.015degrees; and Scan speed 2 degree/min.

Differential Scanning calorimetry (DSC) was carried out on a TAInstruments Differential Scanning calorimetry, Discovery DSC2500 withautosampler. The DSC instrument conditions were as follows: 20-300° C.at 10° C./min; Tzero aluminum sample pan and lid; and nitrogen gas flowat 50 mL/min.

Thermogravimetric analysis (TGA) was carried out on a TA InstrumentsThermogravimetric Analyzer, Discovery TGA5500 with autosampler. Thegeneral experimental conditions for TGA were: ramp from 25° C. to 300°C. at 10° C./min; nitrogen purge gas flow at 25 mL/min; platinum sampleholder.

Example 1 Preparation of Compound 1

Step 1. tert-Butyl((3S,5S)-1-(4-fluoro-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 1,4-difluoro-2-nitrobenzene (68.2 μL, 0.629 mmol) andtert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (136 mg,0.629 mmol) in DMSO (2.5 mL) was treated with triethylamine (131 μL,0.943 mmol) and the reaction mixture was heated to 80° C. for 3 hrs.After cooling to r.t., the reaction mixture was diluted with DCM, washedwith brine, dried over sodium sulfate and the solvent was evaporatedunder vacuum. The obtained crude product was used in the next stepwithout further purification. LCMS calculated for C₁₂H₁₅FN₃O₅(M+H-C₄H₈)⁺: m/z=300.1; found 300.1.

Step 2. tert-Butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A mixture of tert-butyl((3S,5S)-1-(4-fluoro-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(100 mg, 0.281 mmol), iron (79 mg, 1.407 mmol) and ammonium chloride (90mg, 1.7 mmol) in THF (2 mL), water (2 mL) and methanol (2 mL) wasstirred at 60° C. for 3 hrs. After cooling to r.t., the mixture wasfiltered through a plug of Celite and diluted with DCM. The organicphase was separated, washed with brine, dried over sodium sulfate andthe solvents were evaporated under vacuum. The obtained crude productwas used in the next step without further purification. LCMS calculatedfor Ci6H25FN303 (M+H)⁺: m/z =326.2; Found: 326.2.

Step 3.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Compound 1)

HATU (175 mg, 0.461 mmol) was added to a solution of tert-butyl((3S,5S)-1-(2-amino-4-fluorophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(100 mg, 0.307 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (the product ofExample 1, step 1, 76 mg, 0.307 mmol) and DIPEA (107 μL, 0.615 mmol) inDMF (2 mL). The reaction mixture was stirred at r.t. for 30 mins, thenwater was added and the precipitated product was collected byfiltration, washed with water and air dried. The solid was dissolved inTFA and the resulting solution was stirred at r.t. for 10 mins. Thesolution was then diluted with acetonitrile and purified with prep-LCMS.LCMS calculated for C₂₃H₂₄F₂N₅O₃ (M+H)⁺: m/z=456.2; Found: 456.3.Prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% NH₄OH, at flow rate of 60 mL/min).Free base: 1H NMR (600 MHz, DMSO-d₆) δ 9.34-9.18 (m, 1H), 8.25-8.19 (m,1H), 8.18-8.14 (m, 1H), 7.60-7.49 (q, J=7.7 Hz, 1H), 7.49-7.43 (m, 1H),7.08-7.02 (d, J=8.4 Hz, 1H), 7.02-6.94 (m, 2H), 3.78-3.71 (s, 3H),3.38-3.30 (t, J=6.4 Hz, 1H), 3.30-3.23 (m, 1H), 3.23-3.17 (m, 1H),3.17-3.10 (dd, J=11.1, 6.1 Hz, 1H), 2.95-2.88 (t, J=7.4 Hz, 1H),2.88-2.80 (m, 1H), 2.35-2.25 (dt, J=14.1, 8.0 Hz, 1H), 1.25-1.12 (m, 1H)ppm. Prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) TFAsalt: 1H NMR (600 MHz, DMSO-d6) δ10.78-10.58 (s, 1H), 9.32-9.20 (d,J=5.0 Hz, 1H), 8.24-8.08 (m, 2H), 7.93-7.77 (br, J=5.7 Hz, 2H),7.62-7.53 (td, J=8.4, 6.8 Hz, 1H), 7.53-7.46 (dd, J=8.8, 5.7 Hz, 1H),7.10-7.02 (m, 2H), 7.02-6.93 (t, J=8.8 Hz, 1H), 3.82-3.73 (s, 3H),3.75-3.67 (m, 1H), 3.59-3.51 (m, 1H), 3.30-3.15 (m, 4H), 2.44-2.35 (ddd,J=13.6, 9.1, 7.2 Hz, 1H), 1.81-1.71 (dt, J=13.5, 4.3 Hz, 1H) ppm.

Example 2 Preparation of Compound 2

Step 1. tert-Butyl((3S,5S)-1-(5-bromo-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of 4-bromo-2-fluoro-1-nitrobenzene (532 mg, 2.42 mmol) andtert-butyl ((3S,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate (523 mg,2.42 mmol) in DMSO (8 mL) was treated with triethylamine (506 3.63 mmol)and the reaction mixture was heated to 80° C. for 2 hr. After cooling tor.t., water was added and the precipitated product was collected byfiltration, washed with water and air dried. It was used in the nextstep without further purification. LCMS calculated for C₁₂H₁₅BrN₃O₅(M+H−C₄H₈)⁺: m/z=360.0/362.0; found 360.0/362.0.

Step 2. tert-Butyl((3S,5S)-1-(2-amino-5-bromophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A mixture of tert-butyl((3S,5S)-1-(5-bromo-2-nitrophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(1 g, 2.45 mmol), iron (684 mg, 12.25 mmol) and ammonium chloride (786mg, 14.70 mmol) in THF (5 mL), water (5 mL) and methanol (5 mL) wasstirred at 60° C. for 3 hrs. After cooling to r.t., it was filteredthrough a plug of Celite and diluted with DCM. The organic phase wasseparated, washed with saturated aqueous sodium chloride, dried oversodium sulfate and the solvents were evaporated in vacuo. The obtainedcrude product was used in the next step without further purification.LCMS calculated for C₁₆H₂₅BrN₃O₃ (M+H)⁺: m/z=386.1/388.1; Found:386.1/388.1.

Step 3. tert-Butyl((3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

HATU (1196 mg, 3.15 mmol) was added to a solution of tert-butyl ((3S,5S)-1-(2-amino-5-bromophenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(810 mg, 2.097 mmol),2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxylic acid (the product ofExample 1, step 1, 520 mg, 2.097 mmol) and DIPEA (732 μl, 4.19 mmol) inDMF (5 mL). The reaction mixture was stirred at r.t. for 30 mins, thenwater was added and the precipitated product was collected byfiltration, washed with water and air dried. The solid was used in thenext step without further purification. LCMS calculated forC₂₈H₃₂BrFN₅O₅ (M+H)⁺: m/z=616.2/618.2; Found: 616.2/618.2.

Step 4.N-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide(Compound 2)

A mixture of tert-butyl((3S,5S)-1-(5-bromo-2-(2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamido)phenyl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(10 mg, 0.016 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (9.8mg, 0.043 mmol), Xphos Pd G2 (1.3 mg, 1.6 μmop and potassium phosphate,tribasic (6.7 mg, 0.032 mmol) was combined with 1,4-dioxane (1 mL) andwater (0.1 mL) and the reaction flask was evacuated, back filled withnitrogen, then stirred at 80° C. for 1 hr. The reaction mixture wascooled to r.t., the solvents were evaporated in vacuo and TFA (1 mL) wasadded. The reaction mixture was stirred at r.t. for 10 min, then dilutedwith CH₃CN and water and purified with prep-LCMS. LCMS calculated forC₂₉H₂₇FN₇O₃ (M+H)⁺: m/z=540.2; Found: 540.1. Prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%NH₄OH, at flow rate of 60 mL/min). Free base: ¹H NMR (500 MHz, DMSO-d₆)δ9.33-9.25 (d, J=5.0 Hz, 1H), 8.98-8.93 (s, 1H), 8.84-8.78 (d, J=5.0 Hz,1H), 8.46-8.39 (d, J=8.4 Hz, 1H), 8.22-8.18 (d, J=5.0 Hz, 1H), 8.00-7.92(dd, J=5.1, 0.7 Hz, 1H), 7.67-7.64 (m, 1H), 7.59-7.52 (td, J=8.4, 6.8Hz, 1H), 7.48-7.43 (dd, J=8.3, 2.1 Hz, 1H), 7.11-7.04 (d, J=8.5 Hz, 1H),7.03-6.90 (t, J=8.8 Hz, 1H), 3.85-3.73 (s, 3H), 3.68-3.56 (m, 1H),3.39-3.29 (m, 3H), 3.28-3.22 (d, J=4.8 Hz, 1H), 3.06-2.97 (d, J=5.4 Hz,1H), 2.31-2.18 (dt, J=12.6, 7.5 Hz, 1H), 1.40-1.29 (dt, J=12.7, 6.2 Hz,1H) ppm. Prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min). TFAsalt: ¹H NMR (500 MHz, DMSO-d₆) δ10.66-10.59 (s, 1H), 9.31-9.24 (d,J=5.0 Hz, 1H), 9.03-8.94 (d, J=0.8 Hz, 1H), 8.88-8.78 (d, J=5.0 Hz, 1H),8.34-8.24 (d, J=8.4 Hz, 1H), 8.24-8.17 (d, J=5.0 Hz, 1H), 8.04-7.95 (dd,J=5.1, 0.8 Hz, 1H), 7.92-7.82 (br, J=5.5 Hz, 2H), 7.73-7.65 (d, J=2.0Hz, 1H), 7.61-7.54 (td, J=8.5, 6.9 Hz, 1H), 7.50-7.45 (dd, J=8.4, 2.0Hz, 1H), 7.11-7.05 (d, J=8.5 Hz, 1H), 7.05-6.98 (t, J=8.8 Hz, 1H),3.89-3.82 (m, 1H), 3.81-3.77 (s, 3H), 3.76-3.69 (m, 1H), 3.42-3.21 (m,4H), 2.43-2.31 (m, 1H), 1.90-1.77 (dt, J=13.2, 5.3 Hz, 1H) ppm.

Example 3 Synthesis of Crystalline Form I of Compound 1

Form I of Compound 1 was obtained by stirring 52.63 mg of the amorphousfree base in 1 mL of isopropyl alcohol (IPA) in a 4 mL clear glass vialat room temperature overnight. The crystalline solid was collected byfiltration and air dried.

Form I was confirmed as a crystalline solid according to XRPD analysis.The XRPD pattern of Form I is shown in FIG. 1 and the peak data is givenbelow in Table 1.

TABLE 1 XRPD Peak Data for Free Base Form I. 2-Theta (°) RelativeIntensity (%) 6.7 100 9.1 2.1 9.9 19.9 10.4 5.0 10.9 2.6 13.4 19.7 14.114.2 14.6 12.4 15.5 23.1 15.9 2.4 16.2 5.5 16.5 8.0 16.9 4.4 17.5 6.318.3 20.5 19.2 7.2 19.9 31.5 20.4 36.8 20.9 13.8 21.0 14.3 21.5 3.0 21.99.6 22.2 11.3 22.8 13.3 23.5 9.7 24.4 10.2 25.1 3.5 26.0 2.5 25.5 27.226.0 2.9 26.2 4.5 26.6 5.5 27.4 18.8 28.1 3.5 28.6 4.8 29.5 3.8

DSC analysis of the free base Form I revealed a first endothermic peakwith an onset temperature of 57.3° C. and a maximum at 86.2° C. and asecond endothermic peak with an onset temperature of 182.8° C. and amaximum at 183.4° C. The DSC thermogram is provided in FIG. 2.

TGA analysis of the free base Form I revealed 10.4% weight loss below100° C. and significant weight loss above 200° C. due to decompositionof the sample. The TGA thermogram is provided in FIG. 3.

Example 4 Preparation and Characterization of Compound 1 Phosphate Salt

104.5 mg of Compound 1 was added in 1 mL of methanol in a 4 mL clearglass vial with stirring. To the solution/suspension, 60.2 μL of 4Maqueous phosphoric acid (1.05 eq) was added and mixed well. The solutionwas evaporated at room temperature to dryness. The resultant solid wastreated with 1 mL of water and stirred for 2 hours at room temperature.The solid phosphate salt was collected by filtration and air dried. Thesalt ratio between free base and phosphoric acid was determined to be1.05 by NMR analysis.

The phosphate salt was confirmed as a crystalline solid according toXRPD analysis. The XRPD pattern of the phosphate salt is shown in FIG. 4and the peak data is given below in Table 2.

TABLE 2 XRPD Peak Data for Phosphate Salt. 2-Theta (°) RelativeIntensity (%) 6.3 63.3 6.4 100 7.0 65.3 8.9 22.2 10.7 2.3 11.2 47.8 11.45.4 12.5 60.8 12.8 10.0 14.1 19.1 14.4 13.1 15.4 8.0 15.8 33.0 16.8 10.817.0 33.5 17.2 1.5 18.0 37.1 18.8 11.8 19.2 8.3 19.4 17.3 19.9 64.7 20.317.6 20.7 4.8 20.9 1.1 21.2 21.8 21.6 21.6 21.9 7.3 22.1 4.8 22.6 32.422.9 90.0 23.1 13.6 23.4 6.4 23.7 3.1 23.9 1.9 24.5 48.3 25.2 55.7 26.215.0 26.6 22.1 27.0 19.4 27.5 13.5 28.2 2.3 28.4 15.5 28.9 6.1 29.1 2.129.5 3.0

DSC analysis of phosphate salt revealed a first endothermic peak with anonset temperature of 56.6° C. and a maximum at 92.5° C. and a secondendothermic peak with an onset temperature of 220.3° C. and a maximum at228.9° C. The DSC thermogram is provided in FIG. 5. TGA analysis of thephosphate salt revealed 18.7% weight loss below 100° C. and significantweight loss above 200° C. due to decomposition of the sample. The TGAthermogram is provided in FIG. 6.

Example 5 Preparation and Characterization of Compound 1 HydrochlorideSalt

112.4 mg of Compound 1 was combined with 1 mL of methanol in a 4 mLclear glass vial with stirring. To the solution/suspension, 86.4 μL of3M aqueous HCl (1.05 eq) was added and mixed well. The solution wasevaporated at room temperature to dryness. The resultant solid wastreated with 1 mL of water and stirred for 2 hours at room temperature.The solid hydrochloride salt was collected by filtration and air dried.

The hydrochloride salt was confirmed as a crystalline solid according toXRPD analysis. The XRPD pattern of hydrochloride salt is shown in FIG. 7and the peak data is given below in Table 3.

TABLE 3 XRPD Peak Data for Hydrochloride Salt. 2-Theta (°) RelativeIntensity (%) 4.5 73 6.0 5.0 6.7 100 9.1 25.3 9.7 6.1 10.6 12.1 11.015.0 11.5 0.6 12.1 1.8 12.7 13.8 12.9 3.6 13.5 18.5 13.9 7.1 14.4 1.014.8 2.4 15.5 30.6 16.5 14.0 17.1 22.7 17.2 7.9 18.2 17.2 18.5 1.3 19.210.7 19.5 3.6 20.0 4.1 20.3 3.6 20.9 8.1 21.2 15.4 21.4 11.1 21.8 5.122.2 3.1 22.5 3.0 22.7 20.8 23.2 21.8 23.4 36.3 23.8 4.9 24.2 1.6 24.66.8 25.3 11.3 26.0 7.8 26.8 5.3 27.4 4.3 28.2 6.4 28.6 3.8 28.9 4.9 29.34.8

DSC analysis of the hydrochloride salt revealed a first endothermic peakwith an onset temperature of 106.3° C. and a maximum at 107.2° C. and asecond endothermic peak with an onset temperature of 230.9° C. and amaximum at 232.7° C. An exothermic peak was also observed around160-175° C. The DSC thermogram is provided in FIG. 8.

TGA analysis of the hydrochloride salt revealed 11.2% weight loss below125° C. and significant weight loss above 225° C. due to decompositionof the sample. The TGA thermogram is provided in FIG. 9.

Example 6 Preparation and Characterization of Compound 1 L-Tartrate Salt

98.9 mg of Compound 1 was combined with 2 mL of methanol in a 4 mL clearglass vial with stirring. To the solution/suspension, 37.53 mg ofL-tartaric acid (1.15 eq) was added and mixed well. Solid precipitatedquickly. The resultant suspension was stirred for 1 h at roomtemperature. The solid L-tartrate salt was collected by filtration andair dried. The dried solid was treated with 2 mL of water in a 4 mLclear glass vial and stirred overnight at room temperature. Therecrystallized solid of the L-tartrate salt was collected by filtrationand dried at 30° C. under vacuum overnight. The salt ratio between thefree base and L-tartaric acid was determined to be 1.0 by NMR analysis.

The L-tartrate salt was confirmed as a crystalline solid according toXRPD analysis. The XRPD pattern of the L-tartrate salt is shown in FIG.10 and the peak data is given below in Table 4.

TABLE 4 XRPD Peak Data for L-Tartrate Salt. 2-Theta (°) RelativeIntensity (%) 4.9 29.1 7.5 10.9 7.9 31.7 9.0 5.7 9.8 100 10.0 12.0 10.518.2 12.4 4.4 13.0 3.4 13.7 26.4 14.4 6.3 14.7 23.3 15.1 4.7 15.4 2.715.9 72.1 16.0 63.5 16.5 6.1 16.9 71.6 17.5 7.3 18.1 30.1 18.3 5.4 18.810.7 19.6 71.2 20.2 6.1 20.8 24.8 21.2 19.3 22.4 7.5 23.0 60.2 23.4 7.724.0 13.0 24.7 23.3 24.8 13.9 25.2 10.6 25.9 23.8 26.3 8.0 26.9 8.0 27.74.8 28.2 3.1 28.7 9.9 29.1 1.8 29.6 5.7

DSC analysis of the L-tartrate salt revealed a first endothermic peakwith an onset temperature of 76.4° C. and a maximum at 101.5° C. and asecond endothermic peak with an onset temperature of 213.9° C. and amaximum at 216.6° C. The DSC thermogram is provided in FIG. 11. TGAanalysis of the L-Tartrate salt revealed 6.3% weight loss below 100° C.and significant weight loss above 200° C. due to decomposition of thesample. The TGA thermogram is provided in FIG. 12.

Example 7 Preparation and Characterization of Compound 1 Malate Salt

64.4 mg of Compound 1 was treated with 1 mL of methanol in a 4 mL clearglass vial with stirring. To the solution/suspension, 23.0 mg of(−)-L-malic acid (1.2 eq) was added and mixed well. The resultantsolution was evaporated at room temperature to dryness. The resultantsolid was treated with 1 mL of methanol and stirred for 2 hours at roomtemperature. The solid of the malate salt was collected by filtrationand air dried. The salt ratio between the free base and malic acid wasdetermined to be 1.0 by NMR analysis.

The malate salt was confirmed as a crystalline solid according to XRPDanalysis. The XRPD pattern of the malate salt is shown in FIG. 13 andthe peak data is given below in Table 5.

TABLE 5 XRPD Peak Data for Malate Salt. 2-Theta (°) Relative Intensity(%) 5.2 54.6 7.9 17.8 8.2 6.9 9.3 0.6 10.4 100 11.3 8.0 12.5 5.5 12.87.3 13.4 6.7 14.3 15.7 14.7 5.6 15.8 40.3 16.6 47.6 17.3 3.2 18.0 43.818.3 8.1 19.2 14.5 20.4 5.5 21.0 80.1 21.2 73.2 21.8 3.5 22.9 12.0 23.710.0 24.3 7.6 24.9 11.0 25.4 9.1 25.9 15.7 27.1 8.3 28.1 1.3 28.7 3.129.5 4.8

DSC analysis of the malate salt revealed a first endothermic peak withan onset temperature of 23.7° C. and a maximum at 71.2° C. and a secondendothermic peak with an onset temperature of 195.9° C. and a maximum at198.4° C. The DSC thermogram is provided in FIG. 14.

TGA analysis of the malate salt revealed 1.5% weight loss below 100° C.and significant weight loss above 200° C. due to decomposition of thesample. The TGA thermogram is provided in FIG. 15.

Example 8 Preparation and Characterization of Compound 1 Camsylate Salt

62.17 mg of Compound 1 was treated with 1 mL of methanol in a 4 mL clearglass vial with stirring. To the solution/suspension, 35.4 mg of(1S)-(+)-10-camphorsulfonic acid (1.1 eq) was added and mixed well. Theresultant solution was evaporated at room temperature to dryness. Theresultant solid was treated with 1 mL of water and stirred for 2 hoursat room temperature. The solid of the camsylate salt was collected byfiltration and air dried. The salt ratio between the free base and(1S)-(+)-10-camphorsulfonic acid was determined to be 1.0 by NMRanalysis.

The camsylate salt was confirmed as a crystalline solid according toXRPD analysis. The XRPD pattern of the camsylate salt is shown in FIG.16 and the peak data is given below in Table 6.

TABLE 6 XRPD Peak Data for Camsylate Salt. 2-Theta (°) RelativeIntensity (%) 4.9 90.7 5.9 96.6 8.1 1.8 9.8 17.5 10.1 6.5 10.9 32.4 11.82.7 12.2 25.4 12.8 9.1 13.2 3.1 14.0 15.7 14.4 67.9 15.0 84.0 15.1 10015.7 35.5 16.2 27.9 16.5 28.2 17.6 7.7 18.5 10.1 19.2 4.0 19.8 45.9 20.137.9 20.5 15.8 20.9 24.7 23.0 6.5 23.4 5.7 24.1 3.5 25.8 43.3 26.5 29.627.6 9.2 28.1 4.5 28.8 9.8

DSC analysis of the camsylate salt revealed a first endothermic peakwith an onset temperature of 21.6° C. and a maximum at 64.4° C. and asecond major endothermic peak with an onset temperature of 227.2° C. anda maximum at 235.6° C. The DSC thermogram is provided in FIG. 17.

TGA analysis of the camsylate salt revealed 0.9% weight loss below 150°C. and significant weight loss above 200° C. due to decomposition of thesample. The TGA thermogram is provided in FIG. 18.

Example 9 Preparation and Characterization of Compound 1 Mandelate Salt

65.18 mg of Compound 1 was dissolved in 1 mL of methanol in a 4 mL clearglass vial with stirring. To the solution, 26.58 mg of (S)-(+)-mandelicacid (1.2 eq) was added and mixed well. The resultant solution wasevaporated at room temperature to dryness. The resultant oil was treatedwith 1 mL of water and stirred for 2 hours at room temperature. Thesolid of the mandelate salt was collected by filtration and air dried.The salt ratio between the free base and (S)-(+)-mandelic acid wasdetermined to be 1.1 by NMR analysis.

The mandelate salt was confirmed as a crystalline solid according toXRPD analysis. The XRPD pattern of the mandelate salt is shown in FIG.19 and the peak data is given below in Table 7.

TABLE 7 XRPD Peak Data for Mandelate Salt. 2-Theta (°) RelativeIntensity (%) 4.2 100 5.0 33.2 5.4 30.4 5.8 46.6 6.9 32.1 8.4 2.6 8.91.6 10.1 13.3 10.4 2.6 11.0 5.4 12.0 8.1 12.6 11.2 13.0 5.8 13.4 8.413.9 16.8 14.2 25.1 15.0 23.6 15.3 28.9 16.1 7.2 16.4 16.3 17.1 15.317.6 8.0 18.0 2.4 18.7 20.0 19.0 42.4 19.6 36.7 20.1 10.1 20.2 13.2 20.73.2 21.0 10.8 21.6 15.7 22.0 10.8 22.3 16.2 23.0 9.6 23.8 13.9 24.4 10.525.0 17.2 25.5 15.7 25.9 13.4 26.3 13.7 26.9 4.1 27.3 13.3 27.7 10.028.1 3.4 28.4 3.8 29.3 1.9

DSC analysis of the mandelate salt revealed a first endothermic peakwith an onset temperature of 81.5° C. and a maximum at 92.8° C. and asecond endothermic peak with an onset temperature of 187.5° C. and amaximum at 217.4° C. The DSC thermogram is provided in FIG. 20.

TGA analysis of the mandelate salt revealed 4.6% weight loss below 150°C. and significant weight loss above 170° C. due to decomposition of thesample. The TGA thermogram is provided in FIG. 21.

Example 10 Preparation and Characterization of Compound 1 Citrate Salt

A 2 L round bottom flask was charged with Compound 1 (59.7 g, 131 mmol)and acetone (600 mL). The mixture was stirred at ambient temperature for30 min until a solution was obtained. Citric acid, monohydrate (28.9 g,138 mmol) was charged as a solution in 60 mL water. The mixture wasstirred at room temperature for 16 h. The precipitate was collected byvacuum filtration and the wet cake was washed with 3 x 50 mL acetone(also used to rinse the vessel), then dried by pulling vacuum throughthe wet cake for 5 h. The solids were then dissolved in water at 80° C.(about 20 volumes needed to dissolve most of the sample). The mixturewas polish filtered, then slowly cooled. After 15 h, the precipitate wascollected by filtration. The wet cake was washed with 20 mL of coldwater, then with 100 mL of heptane and dried by pulling vacuum throughthe wet cake for 5 h. The pale yellow sample was dried in a 50° C.vacuum oven for 48 h to yield 66.2 g of the citrate salt (78% yield).MUD conforms. HPLC purity=99.1% at 254 nm. KF=<0.1%. MS: 456.2 (M+H)⁺.¹H NMR (600 MHz, DMSO-d₆) d 10.72 (s, 1H), 9.28 (d, J=5.0 Hz, 1H),8.20-8.13 (m, 2H), 7.60-7.48 (m, 2H), 7.09-6.95 (m, 3H), 3.77 (s, 3H),3.71-3.68 (br m, 1H), 3.55-3.51 (br m, 1H), 3.27-3.15 (m, 4H), 2.59-2.55and 2.52-2.48 (citrate peaks, 4H), 2.45-2.36 (m, 1H), 1.77-1.71 (m, 1H).

The citrate salt was confirmed as a crystalline solid according to XRPDanalysis. The salt ratio between the free base and citric acid wasdetermined to be 1.0 by NMR analysis. The XRPD pattern of the citratesalt is shown in FIG. 22 and the peak data is given below in Table 8.

TABLE 8 XRPD Peak Data for Citrate Salt. 2-Theta (°) Relative Intensity(%) 6.1 1.1 6.6 0.3 7.3 26.9 9.0 50.4 11.3 2.6 12.2 6.4 13.3 2.1 13.654.2 13.9 9.9 14.6 1.3 14.9 12.6 16.2 4.0 16.4 5.7 16.6 26.8 17.0 2.317.8 1.3 18.1 51.7 18.3 100 18.8 12.6 19.5 40.9 20.1 33.9 20.4 9.4 20.947.6 21.6 23.8 21.8 12.8 22.0 4.2 22.4 30.8 22.7 10.0 23.5 9.5 23.8 2.424.1 10.2 24.5 29.4 24.9 2.8 25.3 23.6 25.7 16.3 26.4 7.6 26.8 8.4 27.324.2 27.5 4.7 28.0 34.7 28.4 4.5 28.9 1.0 29.1 0.4 29.5 16.3 29.8 13.2

DSC analysis of the citrate salt revealed one major endothermic peakwith an onset temperature of 205.8° C. and a maximum at 210.0° C. TheDSC thermogram is provided in FIG. 23.

TGA analysis of the citrate salt revealed 0.8% weight loss below 200° C.and significant weight loss above 200° C. due to decomposition of thesample. The TGA thermogram is provided in FIG. 24.

Example 11 Compound 2 Phosphate Salt

A 3 L round bottom flask was charged with Compound 2 (21.5 g, 39.8 mmol)and acetone (1000 mL). The resulting solution was stirred at roomtemperature for 15 min. A solution of 1 M aqueous phosphoric acid (41.8mL, 41.8 mmol) was added over 5 min. The resulting thick slurry wasstirred at room temperature for 16 h then vacuum filtered. The wet cakewas washed with 3×50 mL acetone (also used to rinse the vessel), thenwashed with 100 mL heptane and dried by pulling vacuum through the wetcake for 5 h. The pale yellow sample was dried in a 50° C. vacuum ovenfor 48 h to yield 25.1 g of the monophosphate dihydrate salt (94%yield). XRPD conforms. HPLC purity=98.7% at 254 nm. KF=5.2%. MS: 540.2(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) d 10.78 (br s, 1H), 9.29 (d, J=5.0 Hz,1H), 8.96 (d, J=0.9 Hz, 114), 8.81 (d, J=5.0 Hz, 1H), 8.36 (d, J=8.4 Hz,1H), 8.19 (d, J=5.0 Hz, 1H), 7.97 (dd, J=5.1, 0.8 Hz, 1H), 7.64 (d,J=2.1 Hz, 1H), 7.60-7.50 (td, J=8.5, 6.9 Hz, 1H), 7.49-7.43 (dd, J=8.3,2.0 Hz, 1H), 7.11-6.96 (m, 2H), 3.79 (s, 3H), 3.75 (br m, 1H), 3.57-3.48(br m, 1H), 3.33-3.26 (m, 2H), 3.24-3.18 (m, 2H), 2.36-2.27 (dt, J=13.2,7.8 Hz, 1H), 1.78-1.69 (dt, J=12.1, 5.2 Hz, 1H). Phosphate salt ratiowas determined by ³¹P NMR using triphenyl phosphate as an internalstandard.

The phosphate salt was confirmed as a crystalline solid according toXRPD analysis. The salt ratio between the free base and phosphoric acidwas determined to be 1.0 by NMR analysis. The XRPD pattern of thephosphate salt is shown in FIG. 25 and the peak data is given below inTable 9.

TABLE 9 XRPD Peak Data for Phosphate Salt. 2-Theta (°) RelativeIntensity (%) 5.9 11.8 6.3 5.5 6.7 60.6 10.2 39.5 11.0 11.0 11.9 15.612.6 4.2 13.4 24.1 13.7 1.1 14.5 52.7 15.5 37.1 15.9 24.7 16.1 2.9 16.540.8 17.4 36.3 18.0 100 18.3 3.2 18.8 6.8 19.0 18.6 19.2 28.8 19.8 19.020.0 15.1 20.4 57.3 21.2 13.3 21.6 0.7 22.0 25.7 22.2 26.0 23.0 37.923.3 65.2 23.6 26.2 24.0 6.9 24.7 42.6 25.2 15.5 25.7 11.5 26.2 23.026.5 6.2 27.1 10.7 27.3 7.4 27.5 6.6 28.0 21.5 28.3 17.3 28.9 4.6 29.311.6 29.5 6.6

The Compound 2 phosphate salt was characterized by DSC. DSC analysis ofthe phosphate salt revealed one major endothermic peak with an onsettemperature of 76.8° C. and a maximum at 115.5° C. and a second majorendothermic peak with an onset temperature of 194.8° C. and a maximum at199.5° C. A small endothermic peak with a maximum at 179.7° C. was alsoobserved. The DSC thermogram is provided in FIG. 26.

TGA analysis of the phosphate salt revealed 5.0% weight loss below 125°C. and significant weight loss above 175° C. due to decomposition of thesample. Water contert was determined to be 5.2-5.3% by Karl Fischer,which suggests the phosphate salt is possibly a di-hydrate. The TGAthermogram is provided in FIG. 27.

Example 12 Compound 2 Hydrochloride Salt

53.83 mg of Compound 2 free base was dissolved in 1 mL of methanol in a4 mL clear glass vial with stirring. To the solution, 35 μL of aqueous3M HCl (1.05 eq) was added and mixed well. The solution was evaporatedwithout cap at room temperature to dryness. To the resulted solid, 1 mLof MeOH was added and stirred for 2 hours at room temperature. The solidof the hydrochloride salt was collected by filtration and air dried.

The hydrochloride salt was confirmed as a crystalline solid according toXRPD analysis. The XRPD pattern of the hydrochloride salt is shown inFIG. 28 and the peak data is given below in Table 10.

TABLE 10 XRPD Peak Data for Hydrochloride Salt. 2-Theta (°) RelativeIntensity (%) 6.2 100 6.8 21.1 11.2 17.1 12.0 0.2 12.5 9.5 13.6 13.213.8 7.0 14.7 0.3 16.3 0.3 16.8 11.3 17.3 33.2 17.7 0.8 18.4 12.6 18.33.5 19.5 0.7 19.9 4.9 20.2 3.1 20.4 2.6 21.1 4.9 21.3 8.4 21.6 10.8 22.311.7 22.7 4.5 23.1 2.3 23.3 4.4 24.1 7.9 23.7 1.6 25.1 6.2 25.3 6.7 25.86.3 26.6 1.0 27.2 1.9 27.5 5.7 27.9 7.6 29.2 1.8 29.6 0.7

DSC analysis of the hydrochloride salt revealed first endothermic peakwith an onset temperature of 121.9° C. and a maximum at 130.3° C. and asecond endothermic peak with an onset temperature of 243.9° C. and amaximum at 249.3° C. The DSC thermogram is provided in FIG. 29.

TGA analysis of the hydrochloride salt revealed 2.9% weight loss below150° C. and significant weight loss above 225° C. due to decompositionof the sample. The TGA thermogram is provided in FIG. 30.

Example A HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μLof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). Kivalues were determined.

Compounds of the present disclosure, as exemplified in Examples 6 and 42of U.S. patent application Ser. No. 16/278,865 (published as US PatertPublication No. 2019/0382380), showed the K_(i) values in the followingranges: +=Ki≤100 nM; ++=100 nM<Ki≤500 nM; +++=500 nM<Ki≤5000 nM.

TABLE 11 Compound Ki, nM 1 + 2 +

Example B p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/mL. The Jurkat cells(35 mL) are dispensed into each well in a 384 well plate. Test compoundsare diluted with cell culture media for 40-fold dilution (adding 39 mLcell culture media into 1 mL compound). The Jurkat cells in the wellplate are treated with the test compounds at various concentrations(adding 5 ul diluted compound into 35 mL Jurkat cells and starting from3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed bytreatment with anti-CD3 (5 mg/mL, OKT3 clone) for 30 min. A 1:25dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with4×Lysis Buffer(LB) is prepared and 15 mL of the 4×LB buffer withblocking reagent is added into each well and incubated at roomtemperature for 45 min with gentle shaking. The cell lysate (16 mL) isadded into a Greiner white plate, treated with p-SLP76 ser376HTRFreagents (2 mL donor, 2 ul acceptor) and incubated at 4° C. forovernight. The homogeneous time resolved fluorescence (HTRF) is measuredon a PHERAstar plate reader the next day. IC₅₀ determination isperformed by fitting the curve of percent inhibition versus the log ofthe inhibitor concentration using the GraphPad Prism 5.0 software.

Example C Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD³/_(a)nti-CD28 beads in the presenceor absence of testing compounds at various concentrations. 16 μL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25− T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/mL in RPMI-1640 medium.100 mL of CFSE-labeled T-cells are mixed with or without 50 mL ofCD4+/CD25+ regulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C., 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including all patert,patert applications, and publications, cited in the present applicationis incorporated herein by reference in its entirety.

1-47. (canceled)
 48. A unit dosage form comprising a solid form ofCompound 1 having the formula:

wherein the solid form has crystalline Form I, and wherein the solidform has at least one characteristic X-ray powder diffraction (“XRPD”)peak selected from about 6.7, about 9.9, about 13.4, about 14.1, about15.5, about 18.3, about 19.9, and about 20.4 degrees 2-theta.
 49. Theunit dosage form of claim 48, wherein the solid form has at least onecharacteristic XRPD peak selected from about 6.7, about 9.9, about 13.4,and about 15.5 degrees 2-theta.
 50. The unit dosage form of claim 48,wherein the solid form has an XRPD pattern with characteristic peaks assubstantially shown in FIG.
 1. 51. The unit dosage form of claim 48,wherein the solid form exhibits a DSC thermogram having endotherm peaksat temperatures of about 86° C. and about 183° C.
 52. The unit dosageform of claim 48, wherein the solid form has a DSC thermogramsubstantially as depicted in FIG.
 2. 53. The unit dosage form of claim48, wherein the solid form has a TGA thermogram substantially asdepicted in FIG.
 3. 54. A unit dosage form comprising a salt which is anacid salt ofN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,having the structure:

wherein the acid is selected from phosphoric acid, hydrochloric acid,L-(+)-tartaric acid, malic acid, camphorsulfonic acid, mandelic acid,and citric acid, wherein the salt is crystalline, and wherein: thephosphoric acid salt of Compound 1 has at least one characteristic XRPDpeak selected from about 6.3, about 6.4, about 7.0, about 8.9, about11.2, about 12.5, about 19.9, and about 22.9 degrees 2-theta; thehydrochloric acid salt of Compound 1 has at least one characteristicXRPD peak selected from about 6.7, about 9.1, about 11.0, about 12.7,about 13.5, about 15.5, about 17.1, and about 23.4 degrees 2-theta; theL-(+)-tartaric acid salt of Compound 1 has at least one characteristicXRPD peak selected from about 4.9, about 7.9, about 9.8, about 15.9,about 16.9, about 19.6, and about 23.0 degrees 2-theta; the malic acidsalt of Compound 1 has at least one characteristic XRPD peak selectedfrom about 5.2, about 7.9, about 10.4, about 14.3, about 15.8, about16.6, about 18.0, about 21.0, and about 21.2 degrees 2-theta; thecamphorsulfonic acid salt of Compound 1 has at least one characteristicXRPD peak selected from about 4.9, about 5.9, about 10.9, about 14.4,about 15.0, about 15.1, about 19.8, about 20.1, and about 25.8 degrees2-theta; the mandelic acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 4.2, about 5.0, about 5.4,about 5.8, about 6.9, about 14.2, about 15.3, about 19.0, and about 19.6degrees 2-theta; and the citric acid salt of Compound 1 has at least onecharacteristic XRPD peak selected from about 7.3, about 9.0, about 13.6,about 16.6, about 18.1, about 18.3, about 19.5, about 20.1, and about20.9 degrees 2-theta.
 55. The unit dosage form of claim 54, wherein thesalt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidephosphate.
 56. The unit dosage form of claim 54, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidehydrochloride.
 57. The unit dosage form of claim 54, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamideL-tartrate.
 58. The unit dosage form of claim 54, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidemalate.
 59. The unit dosage form of claim 54, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidecamsylate.
 60. The unit dosage form of claim 54, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidemandelate.
 61. The unit dosage form of claim 54, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-5-fluorophenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidecitrate.
 62. The unit dosage form of claim 55, wherein the salt has anX-ray powder diffraction pattern with characteristic peaks assubstantially shown in FIG.
 4. 63. The unit dosage form of claim 56,wherein the salt has an X-ray powder diffraction pattern withcharacteristic peaks as substantially shown in FIG.
 7. 64. The unitdosage form of claim 57, wherein the salt has an X-ray powderdiffraction pattern with characteristic peaks as substantially shown inFIG.
 10. 65. The unit dosage form of claim 58, wherein the salt has anX-ray powder diffraction pattern with characteristic peaks assubstantially shown in FIG.
 13. 66. The unit dosage form of claim 59,wherein the salt has an X-ray powder diffraction pattern withcharacteristic peaks as substantially shown in FIG.
 16. 67. The unitdosage form of claim 60, wherein the salt has an X-ray powderdiffraction pattern with characteristic peaks as substantially shown inFIG.
 19. 68. The unit dosage form of claim 61, wherein the salt has anX-ray powder diffraction pattern with characteristic peaks assubstantially shown in FIG.
 22. 69. A unit dosage form comprising a saltwhich is an acid salt ofN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamide,having the structure:

wherein the acid is selected from phosphoric acid and hydrochloric acid,wherein the salt is crystalline, and wherein: the phosphoric acid saltof Compound 2 has at least one characteristic XRPD peak selected fromabout 5.9, about 6.7, about 10.2, about 13.4, about 14.5, about 15.5,about 16.5, about 17.4, and about 18.0 degrees 2-theta; and thehydrochloric acid salt of Compound 2 has at least one characteristicXRPD peak selected from about 6.2, about 6.8, about 11.2, about 12.5,about 13.6, about 17.3, about 18.4, about 21.6, and about 22.3 degrees2-theta.
 70. The unit dosage form of claim 69, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidephosphate.
 71. The unit dosage form of claim 69, wherein the salt isN-(2-((2S,4S)-4-Amino-2-(hydroxymethyl)pyrrolidin-1-yl)-4-(4-cyanopyridin-3-yl)phenyl)-2-(2-fluoro-6-methoxyphenyl)pyrimidine-4-carboxamidehydrochloride.
 72. The unit dosage form of claim 70, wherein the salthas an X-ray powder diffraction pattern with characteristic peaks assubstantially shown in FIG.
 25. 73. The unit dosage form of claim 71,wherein the salt has an X-ray powder diffraction pattern withcharacteristic peaks as substantially shown in FIG. 28.